Comprehensive Physiology Wiley Online Library

Renal Chloride Channels in Relation to Sodium Chloride Transport

Full Article on Wiley Online Library



ABSTRACT

The many mechanisms governing NaCl absorption in the diverse parts of the renal tubule have been largely elucidated, although some of them, as neutral NaCl absorption across the cortical collecting duct or regulation through with‐no‐lysine (WNK) kinases have emerged only recently. Chloride channels, which are important players in these processes, at least in the distal nephron, are the focus of this review. Over the last 20‐year period, experimental studies using molecular, electrophysiological, and physiological/functional approaches have deepened and renewed our views on chloride channels and their role in renal function. Two chloride channels of the ClC family, named as ClC‐Ka and ClC‐Kb in humans and ClC‐K1 and ClC‐K2 in other mammals, are preponderant and play complementary roles: ClC‐K1/Ka is mainly involved in the building of the interstitial cortico‐medullary concentration gradient, while ClC‐K2/Kb participates in NaCl absorption in the thick ascending limb, distal convoluted tubule and the intercalated cells of the collecting duct. The two ClC‐Ks might also be involved indirectly in proton secretion by type A intercalated cells. Other chloride channels in the kidneys include CFTR, TMEM16A, and probably volume‐regulated LRRC8 chloride channels, whose function and molecular identity have not as yet been established. © 2019 American Physiological Society. Compr Physiol 9:301‐342, 2019.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Ca2+‐activated, volume‐regulated and hyperpolarization‐activated whole‐cell chloride currents obtained in isolated rat parotid acinar cells. (A) Ca2+‐dependent currents. Note the large relaxing currents at the onset and offset of the voltage pulses. These components tend to disappear when calcium concentration maximally activates the currents (not shown). (B) volume‐regulated currents. Note the negative relaxing current at the onset of large positive voltage pulses. (C) hyperpolarization‐activated currents. These inwardly rectifying currents are far less frequently encountered that the other classical chloride currents mentioned here. The currents elicited by negative voltages steps are largely predominant over currents at positive voltages. Note the large relaxation component at negative voltages. In all cases, the relaxation times appear to have long duration (see the time scale). In all cases, the holding potential was −50 mV and square pulses were delivered to reach voltages of −100 to +100 mV in 20 mV steps. From Arreola et al., J Physiol 490 (Pt 2): 351‐362, 1996, © 1996 publisher John Wiley and Sons, with permission (12).
Figure 2. Figure 2. Schematic depictions of the closed and opened conformation of the selectivity filter of EcClC. In the closed conformation (left hand side) Sint and Scen are occupied by Cl ions (red circles), while Sext is occupied by the side chain of E148. An open conformation with E148 flipped out of Sext into the extracellular vestibule and the site occupied by a third Cl ion is shown on the right. E148 is in red and H‐bonds are shown by dashed lines. See text for further description. From Dutzler et al., Science 300: 108‐112, 2003 (91). Reprinted with permission from AAAS.
Figure 3. Figure 3. Structure of bClC‐K channel as obtained by cryo‐EM. A comparison of bCLC‐K (gray and magenta) and CmClC (cyan) is shown. Transmembrane domain of the red alga ClC exchanger CmClC monomer was superimposed onto that of bClC‐K. α‐Helices are shown as cylinders. The dashed line separates the transmembrane TM (TMD) from the cytosolic (CTD) domains. Indicated is the skew in the twofold axis between the CTDs with respect to that of the TMDs domains (20°). Conformational differences at the subunit interface and tilting of the CTD tilting suggest some plasticity between structural components of ClCs. Reprinted by permission from Springer Nature from Park et al., Nature 541: 500‐505, 2017 (295).
Figure 4. Figure 4. Models for ion transport mechanisms in ClC channels. (A) General architecture of ClC proteins. F348 and I356 are labelled according to residue number in EcClC exchanger. (B) Model for hClC‐1 channel based on its cryo‐EM structure (296). The conformation of the C‐D loop is unaltered from that of exchanger ClCs but there is a lowered kinetic barrier to the passage of Cl. Low affinity at Scen is consistent with rapid Cl permeation. The structure corresponds to a depolarized situation (no voltage applied in the isolated protein). In situ, at negative resting membrane potential, hence in a closed state, Glugate side chain may occupy Sext or Scen as in the exchangers. (C) Model for ClC‐K channels. No outer gate is present as Glugate is replaced by a valine residue while a removed and flip‐down of SerC largely reduces the kinetic barrier. Sext (shown empty) and Scen have weaker Cl binding affinity than in the exchangers. Schematic drawings are some of those appearing in Figure 7 of Park et al., Elife 7: 2018 (296) and are taken with permission.
Figure 5. Figure 5. Two different conformations of bClC‐K dimer structure. The two subunits of one of the conformations (class 2 model, red and green) are shown superimposed on the other (class 1 model, gray) after superposition of the CTDs. α‐Helices are represented as cylinders. Drawing on the left, the structures viewed from the extracellular side. Right, a lateral view. TMD and CTD are transmembrane and cytosolic domains respectively. Reprinted by permission from Springer Nature from Park et al., Nature 541: 500‐505, 2017 (295).
Figure 6. Figure 6. Recording of a 45‐pS chloride channel of the ClC‐K1 type. Single‐channel recording (A) and current‐voltage relationship (B) from one cell‐attached patch obtained on the basolateral membrane of mouse TAL. In the cell‐attached configuration, the clamp potential Vc superimposes on the spontaneous membrane potential, hyperpolarizing or depolarizing membrane patch for negative or positive Vc, respectively. Single‐channel record traces are shown at various Vc. The dotted line marked C indicates the level of current for which the two channels present on this patch are closed. [From Paulais & Teulon, J Membr Biol 113: 253‐260, 1990, ©1990 Springer Nature publisher, with permission. Ref. (299)]
Figure 7. Figure 7. A 10‐pS chloride channel of the ClC‐K2 type is present at high density in the basolateral membrane. The experiments were performed in cell‐attached patches formed on intercalated cells of the CD. Superfusion of Na‐free solution supplemented with N‐ethylmaleimide (NEM, vertical line and arrow) progressively inhibited channel activity and allowed estimation of closed current level (dashed lines), which was used to calculate time‐averaged current and number of open channels (NPo). Bottom: current records corresponding to segments 1, 2, and 3 at top in expanded time scale. Voltage −80 mV. [From Nissant et al. Am J Physiol Renal Physiol 290: F1421‐1429, 2006. © 2006 the American Society of Physiology, with permission. Ref. (280)].
Figure 8. Figure 8. The 10‐pS chloride channel of the ClC‐K2 type: effects of voltage and intracellular pH. All results shown were obtained in the inside‐out configuration. A and B panels illustrate voltage dependence. (A) Representative current recordings at different values of transmembrane voltage (Vc, given on the right side of each trace). The dashed lines indicate the closed channel current levels. (B) Mean NPo/Vc relationship. C and D panels illustrate the dependence on intracellular pH. (C) Current traces from one membrane patch exposed to pHi 7.0–8.2. For clarity, the traces were superimposed, the dashed line indicating the closed channel current level that applies to the recordings at all three pHi values. The respective NPo values are given on the right side of each trace. (D) Activity vs. pHi. Dose‐response relationship. [With permission from ©Pinelli et al. 2016, originally published in the Journal of General Physiology. https://doi:10.1085/jgp.201611623. Ref. (319)].
Figure 9. Figure 9. CFTR chloride channel in the apical membrane of mouse principal cells (CCD). (A) Current recording in the cell‐attached mode (Vc = 40 mV) before and during exposure to 10 μmol/L Forskolin and 1 mmol/L IBMX to increase cyclic AMP. (B) Current recording in the inside‐out configuration (Vc = 80 mV) showing the stimulatory effect of 50 nmol/L PKA. Note that MgATP alone had little effect. [With permission from Lu et al. Proc Natl Acad Sci U S A 107: 6082‐6087, 2010. © 2010 National Academy of Sciences. Ref. (242)]
Figure 10. Figure 10. ClC‐K localization along the renal tubule in Clnk2+/+ using Clcnk2−/− mouse tissue as a negative control. The anti‐ClC‐K antibody recognizes ClC‐K1 and ClC‐K2 (labelled in green). Tubular markers (in red) include NKCC2 for CTAL and MTAL, NCC for the DCT and pendrin for type B intercalated cells. In Clcnk2−/− tissue there is no ClC‐K staining in the CTAL and DCT, or in type B intercalated cells. This suggests that ClC‐K1 is absent or present at very low density in these segments. In contrast, ClC‐K staining is still apparent in the MTAL of Clcnk2−/− mice. Scale bar = 25 μm. [Reproduced from Hennings et al. J Am Soc Nephrol 28: 209‐217, 2017. © 2017 The American Society of Nephrology, with permission. Ref. (156)].
Figure 11. Figure 11. Schematic representation of chloride conductance and chloride channels along the renal tubule. (A) Chloride conductance as estimated from microelectrode measurements in various parts of the renal tubule. Data are mostly derived from experiments in the rabbit kidney using the isolated, microperfused technique. Note that chloride conductance is present all along the nephron on the basolateral side except in the IMCD. On the apical side, chloride conductance has been found mainly in the ATL and to a lower extent in the collecting duct. “basolateral VRAC” refers to chloride conductance activated by hypoosmolarity. (B) The population of chloride channels as deduced from single‐channel current measurements using the patch‐clamp method on renal tubular fragments in the mouse. Four types of chloride channels have been identified, ClC‐K1, ClC‐K2 and pseudo CFTR on the basolateral side, CFTR on the apical side. (C) Distribution of ClC‐K1 and ClC‐K2 along the renal tubule as derived from immunostaining data. It should be noted that the patch‐clamp approach is more sensitive than immunofluorescence since it allowed detecting ClC‐K1 in the CTAL and the intercalated cells at low frequency while ClC‐K1 was undetectable in Clcnk2‐/‐ mice using immunofluorescence.
Figure 12. Figure 12. Functional analysis of Clcnk2−/−mice. (A) Both furosemide (FURO, left‐hand panel), an inhibitor of NKCC2, and hydrochlorothiazide (HCTZ, right‐hand panel), a classical inhibitor of NCC, elicit significant natriuresis in Clcnk2+/+ mice while natriuresis is abolished (FURO) or dramatically blunted (HCTZ) in Clcnk2−/−mice. This experiment demonstrates the pivotal role of ClC‐K2 in the TAL and DCT. [Taken from Hennings et al. J Am Soc Nephrol 28: 209‐217, 2017. © 2017 The American Society of Nephrology, with permission. Ref. (156)]. (B) Elevated levels of prostaglandin E2 in Clcnk2−/−mice. Left‐hand panel: PGE2 is increased twofold in Clcnk2−/−mice as compared to WT. Right‐hand panel: the abundance of the inducible COX‐2 protein was highly augmented in the kidneys of Clcnk2−/−mice as compared to WT mice. [Taken from Grill et al. Acta Physiol (Oxf) 218: 198‐211, 2016. © 2016 publisher John Wiley and Sons, with permission. Ref. (141)].
Figure 13. Figure 13. Simplified scheme of NaCl absorption in the proximal tubule. The proximal tubule, first renal segment after the glomerulus, is involved in a plethora of transport processes that cannot be summarized in one cartoon. Here, we focus on the mechanisms implicated in NaCl transport. The transepithelial voltage (VTE) has a value of about −2 mV at the beginning of the segment (early proximal tubule) and reaches a value of about +2 mV in the second part of the proximal tubule (late proximal tubule). Transport systems also have a heterogeneous distribution in the two parts of the proximal tubule. Fundamentally, Na+ absorption at the apical side proceeds via a series of Na+‐coupled cotransporters and the Na+/H+ exchanger NHE3; at the basolateral side, Na+ exit to the interstitium proceeds via the Na+/K+‐ATPase and Na+‐HCO3cotransporter NBCE1. One part of Na+ is absorbed through the paracellular pathway in the second part of the proximal tubule. Cl can be absorbed through the paracellular pathway all along the entire length of the proximal tubule. Nevertheless, one base/Cl exchanger (CFEX) in the apical membrane may allow the entry of chloride into the cell. The exit at the basolateral membrane is not entirely defined but could include a K+‐Cl cotransporter and a Na+‐dependent Cl/HCO3 exchanger. To our knowledge, the molecular identity of these ion transporters has not been deciphered. KCC4 (gene: Slc12a7) has been suggested to underlie the K+‐Cl cotransporter. The Na+/H+ exchanger NHE3 is also of primary importance in the context of HCO3 absorption: within the cell, H+ and HCO3 are formed in the presence of carbonic anhydrase 2 following CO2 hydration in H2CO3; the protons exiting the cell via NHE3 combine with luminal HCO3 to form CO2 in the presence of membrane‐bound carbonic anhydrase 4 while cellular HCO3is taken in charge by the Na+‐HCO3 cotransporter NBCE1 on the basolateral side.
Figure 14. Figure 14. NaCl absorption along the TAL. Ion transport pathways for NaCl absorption in the TAL include: the Na+‐K+‐2Cl cotransporter NKCC2 (gene: Slc12a1), ROMK K+ channel (Kir1.1, gene: Kcnj1) in the apical membrane, Kir4.1/Kir5.1 K+ channels (genes: Kcnj10 and KcnjJ16), slo2.2 K+ channels (gene: Kcnt1) and ClC‐K1 and ClC‐K2 associated to barttin (Clcnk1, Clcnk2 and Bsnd) in the basolateral membrane. There is also another chloride channel called pseudo CFTR in the basolateral membrane that has not been molecularly identified. According to Feraille and Doucet (108), the α1β1 heterodimer is the most abundant Na+/K+‐ATPase along the renal tubule (genes: Atp1a1 and Atp1b1). The TAL is also involved in paracellular absorption of Mg2+ and Ca2+. Finally, let us mention that an additional K+ channel displaying an elementary conductance of 70 pS is present in the apical membrane. It has been proposed that ROMK participates to its formation because it is absent in Kcnj1 −/− mice (244,245).
Figure 15. Figure 15. NaCl absorption along the DCT. Ion transport pathways for NaCl transport in the DCT1 and DCT2 include: the Na+‐Cl cotransporter NCC (gene: Slc12a3), Kir4.1/Kir5.1 K+ channels (genes: Kcnj10 and KcnjJ16) and ClC‐K2/barttin (Clcnk2 and Bsnd). Additionally, the presence of a K+‐Cl cotransporter with unknown molecular identity in the basolateral membrane has been reported. The Na+/H+ exchanger NHE2 (gene: Slc9a2) and formate/Cl exchanger (molecular identity unknown) are more abundant in the DCT1 than in the DCT2; ENaC (formed by α, β and γ subunits; genes: Scnn1a, 1b and 1g, respectively) and Kir1.1 (R, gene: Kcnj1) are restricted to the DCT2. The DCT is also involved in transcellular absorption of Mg2+ (DCT1‐DCT2) and Ca2+ (DCT2) that are not illustrated here (257).
Figure 16. Figure 16. Modulation of the activity of the Na+‐Cl cotransport NCC by Kir4.1/Kir5.1 K+ channel. (A) Inhibition of Kir4.1 depolarizes plasma membrane and decreases the driving force for chloride across the membrane. As a consequence, chloride flux across ClC‐K2 is reduced, [Cl]i augments and the WNK/SPAK SYSTEM is inhibited. NCC activity is inhibited. (B) Stimulation of Kir4.1 hyperpolarizes plasma membrane and increases the driving force for chloride across the membrane. As a consequence, chloride flux across ClC‐K2 is higher, [Cl]i takes a lower value and the WNK4/SPAK SYSTEM is activated. NCC activity is stimulated. Dotted and solid lines represent a diminished and an enhanced function, respectively. Gray font means an inhibition or a decrease. Abbreviation: V, cell voltage; WNK, with‐no‐lysine kinase, SPAK, ste20‐proline‐alanine rich kinase. From Wang WH, Curr Opin Nephrol Hypertens 25: 429‐35, © Wolters Kluwer Health 2016, with permission [Ref. (437)].
Figure 17. Figure 17. NaCl transport across principal and type B intercalated cells in the CNT and CCD. In principal cells, simple arrangement of ion transport systems including Na+/K+‐ATPase and potassium channels (Kir4.1/Kir5.1 and additional K+ channels) in the basolateral membrane, and ENaC and ROMK (Kir1.1) channels in the apical membrane, allow Na+ absorption and K+ secretion, mainly under the control of aldosterone. The lumen‐negative transepithelial voltage generated by electrogenic Na+ absorption drives paracellular absorption of Cl. Type B intercalated cells (B‐IC) mediate NaCl absorption via a complex scheme involving apically located Cl/HCO3 exchanger pendrin (gene: Slc26a4) and Na+‐driven Cl/HCO3 exchanger NDCBE (gene: Slc4a8), and basolateral Na+‐HCO3 cotransporter AE4 (gene: Slc4a9) and ClC‐K2/barttin Cl channels. The absorption of NaCl in type B intercalated cells can only be observed in condition of low‐Na+ diet (high aldosterone). Type B intercalated cells can also secrete HCO3 into the lumen by the means of the apical Cl/HCO3 exchanger pendrin working in tandem with the V‐type H+‐ATPase and ClC‐K2/barttin Cl channels on the basolateral membrane. Type A intercalated cells secrete H+ into the lumen through the apical V‐type H+‐ATPase and H+/K+‐ATPase, which operate in tandem with the basolateral ClC‐K2/barttin Cl channel, the K+‐Cl cotransporter KCC4 (gene: Slc12a7) and the Cl/HCO3 exchangers AE1 (gene: Slc4a1). The H+/K+‐ATPase is also present in the OMCD. The SLC26A7 Cl/HCO3 exchanger (not shown here) is expressed across the basolateral membranes of the OMCD.
Figure 18. Figure 18. NaCl transport in type B intercalated cells is rather energized by vacuolar H+‐ATPase than Na+/K+‐ATPase. Transepithelial Na+ and Cl fluxes were measured on CCD segments isolated from mice fed a Na+‐depleted diet to evaluate the effects of amiloride (10−5 M, ENaC inhibitor), ouabain (10−4 M, Na+/K+‐ATPase inhibitor) and bafilomycin (4.10−8 M, V‐type H+‐ATPase inhibitor). (A) Na+ absorption is inhibited by ∼60% by either amiloride or ouabain. The effects are not additive indicating that the amiloride‐insensitive component is ouabain‐resistant. Cl absorption is not affected by amiloride or ouabain. (B) The amiloride‐insensitive Na+ and Cl fluxes are abolished in the presence bafilomycin. [With permission from Chambrey et al. Proc Natl Acad Sci U S A 110: 7928‐7933, 2013. © 2003 National Academy of Sciences. Ref. (63)].
Figure 19. Figure 19. Modeling ion transport in type B intercalated cells. The type B intercalated cells are endowed with a complex arrangement of ion transport systems allowing bicarbonate secretion and/or NaCl absorption. This figure shows the predicted effects of variations in basolateral membrane chloride conductance (gClC‐K) on net fluxes of Cl through ClC‐K2 (blue), of Na+ through NDCBE (red), and of apical HCO3 (black; left) and on net transcellular Na+, Cl, and HCO3 transport (right). The labels 1 to 3 correspond to relative gClC‐K values of 0, 0.15, and 1, respectively. [With permission from ©Pinelli et al. 2016, originally published in the Journal of General Physiology. https://doi:10.1085/jgp.201611623. Ref. (319)].


Figure 1. Ca2+‐activated, volume‐regulated and hyperpolarization‐activated whole‐cell chloride currents obtained in isolated rat parotid acinar cells. (A) Ca2+‐dependent currents. Note the large relaxing currents at the onset and offset of the voltage pulses. These components tend to disappear when calcium concentration maximally activates the currents (not shown). (B) volume‐regulated currents. Note the negative relaxing current at the onset of large positive voltage pulses. (C) hyperpolarization‐activated currents. These inwardly rectifying currents are far less frequently encountered that the other classical chloride currents mentioned here. The currents elicited by negative voltages steps are largely predominant over currents at positive voltages. Note the large relaxation component at negative voltages. In all cases, the relaxation times appear to have long duration (see the time scale). In all cases, the holding potential was −50 mV and square pulses were delivered to reach voltages of −100 to +100 mV in 20 mV steps. From Arreola et al., J Physiol 490 (Pt 2): 351‐362, 1996, © 1996 publisher John Wiley and Sons, with permission (12).


Figure 2. Schematic depictions of the closed and opened conformation of the selectivity filter of EcClC. In the closed conformation (left hand side) Sint and Scen are occupied by Cl ions (red circles), while Sext is occupied by the side chain of E148. An open conformation with E148 flipped out of Sext into the extracellular vestibule and the site occupied by a third Cl ion is shown on the right. E148 is in red and H‐bonds are shown by dashed lines. See text for further description. From Dutzler et al., Science 300: 108‐112, 2003 (91). Reprinted with permission from AAAS.


Figure 3. Structure of bClC‐K channel as obtained by cryo‐EM. A comparison of bCLC‐K (gray and magenta) and CmClC (cyan) is shown. Transmembrane domain of the red alga ClC exchanger CmClC monomer was superimposed onto that of bClC‐K. α‐Helices are shown as cylinders. The dashed line separates the transmembrane TM (TMD) from the cytosolic (CTD) domains. Indicated is the skew in the twofold axis between the CTDs with respect to that of the TMDs domains (20°). Conformational differences at the subunit interface and tilting of the CTD tilting suggest some plasticity between structural components of ClCs. Reprinted by permission from Springer Nature from Park et al., Nature 541: 500‐505, 2017 (295).


Figure 4. Models for ion transport mechanisms in ClC channels. (A) General architecture of ClC proteins. F348 and I356 are labelled according to residue number in EcClC exchanger. (B) Model for hClC‐1 channel based on its cryo‐EM structure (296). The conformation of the C‐D loop is unaltered from that of exchanger ClCs but there is a lowered kinetic barrier to the passage of Cl. Low affinity at Scen is consistent with rapid Cl permeation. The structure corresponds to a depolarized situation (no voltage applied in the isolated protein). In situ, at negative resting membrane potential, hence in a closed state, Glugate side chain may occupy Sext or Scen as in the exchangers. (C) Model for ClC‐K channels. No outer gate is present as Glugate is replaced by a valine residue while a removed and flip‐down of SerC largely reduces the kinetic barrier. Sext (shown empty) and Scen have weaker Cl binding affinity than in the exchangers. Schematic drawings are some of those appearing in Figure 7 of Park et al., Elife 7: 2018 (296) and are taken with permission.


Figure 5. Two different conformations of bClC‐K dimer structure. The two subunits of one of the conformations (class 2 model, red and green) are shown superimposed on the other (class 1 model, gray) after superposition of the CTDs. α‐Helices are represented as cylinders. Drawing on the left, the structures viewed from the extracellular side. Right, a lateral view. TMD and CTD are transmembrane and cytosolic domains respectively. Reprinted by permission from Springer Nature from Park et al., Nature 541: 500‐505, 2017 (295).


Figure 6. Recording of a 45‐pS chloride channel of the ClC‐K1 type. Single‐channel recording (A) and current‐voltage relationship (B) from one cell‐attached patch obtained on the basolateral membrane of mouse TAL. In the cell‐attached configuration, the clamp potential Vc superimposes on the spontaneous membrane potential, hyperpolarizing or depolarizing membrane patch for negative or positive Vc, respectively. Single‐channel record traces are shown at various Vc. The dotted line marked C indicates the level of current for which the two channels present on this patch are closed. [From Paulais & Teulon, J Membr Biol 113: 253‐260, 1990, ©1990 Springer Nature publisher, with permission. Ref. (299)]


Figure 7. A 10‐pS chloride channel of the ClC‐K2 type is present at high density in the basolateral membrane. The experiments were performed in cell‐attached patches formed on intercalated cells of the CD. Superfusion of Na‐free solution supplemented with N‐ethylmaleimide (NEM, vertical line and arrow) progressively inhibited channel activity and allowed estimation of closed current level (dashed lines), which was used to calculate time‐averaged current and number of open channels (NPo). Bottom: current records corresponding to segments 1, 2, and 3 at top in expanded time scale. Voltage −80 mV. [From Nissant et al. Am J Physiol Renal Physiol 290: F1421‐1429, 2006. © 2006 the American Society of Physiology, with permission. Ref. (280)].


Figure 8. The 10‐pS chloride channel of the ClC‐K2 type: effects of voltage and intracellular pH. All results shown were obtained in the inside‐out configuration. A and B panels illustrate voltage dependence. (A) Representative current recordings at different values of transmembrane voltage (Vc, given on the right side of each trace). The dashed lines indicate the closed channel current levels. (B) Mean NPo/Vc relationship. C and D panels illustrate the dependence on intracellular pH. (C) Current traces from one membrane patch exposed to pHi 7.0–8.2. For clarity, the traces were superimposed, the dashed line indicating the closed channel current level that applies to the recordings at all three pHi values. The respective NPo values are given on the right side of each trace. (D) Activity vs. pHi. Dose‐response relationship. [With permission from ©Pinelli et al. 2016, originally published in the Journal of General Physiology. https://doi:10.1085/jgp.201611623. Ref. (319)].


Figure 9. CFTR chloride channel in the apical membrane of mouse principal cells (CCD). (A) Current recording in the cell‐attached mode (Vc = 40 mV) before and during exposure to 10 μmol/L Forskolin and 1 mmol/L IBMX to increase cyclic AMP. (B) Current recording in the inside‐out configuration (Vc = 80 mV) showing the stimulatory effect of 50 nmol/L PKA. Note that MgATP alone had little effect. [With permission from Lu et al. Proc Natl Acad Sci U S A 107: 6082‐6087, 2010. © 2010 National Academy of Sciences. Ref. (242)]


Figure 10. ClC‐K localization along the renal tubule in Clnk2+/+ using Clcnk2−/− mouse tissue as a negative control. The anti‐ClC‐K antibody recognizes ClC‐K1 and ClC‐K2 (labelled in green). Tubular markers (in red) include NKCC2 for CTAL and MTAL, NCC for the DCT and pendrin for type B intercalated cells. In Clcnk2−/− tissue there is no ClC‐K staining in the CTAL and DCT, or in type B intercalated cells. This suggests that ClC‐K1 is absent or present at very low density in these segments. In contrast, ClC‐K staining is still apparent in the MTAL of Clcnk2−/− mice. Scale bar = 25 μm. [Reproduced from Hennings et al. J Am Soc Nephrol 28: 209‐217, 2017. © 2017 The American Society of Nephrology, with permission. Ref. (156)].


Figure 11. Schematic representation of chloride conductance and chloride channels along the renal tubule. (A) Chloride conductance as estimated from microelectrode measurements in various parts of the renal tubule. Data are mostly derived from experiments in the rabbit kidney using the isolated, microperfused technique. Note that chloride conductance is present all along the nephron on the basolateral side except in the IMCD. On the apical side, chloride conductance has been found mainly in the ATL and to a lower extent in the collecting duct. “basolateral VRAC” refers to chloride conductance activated by hypoosmolarity. (B) The population of chloride channels as deduced from single‐channel current measurements using the patch‐clamp method on renal tubular fragments in the mouse. Four types of chloride channels have been identified, ClC‐K1, ClC‐K2 and pseudo CFTR on the basolateral side, CFTR on the apical side. (C) Distribution of ClC‐K1 and ClC‐K2 along the renal tubule as derived from immunostaining data. It should be noted that the patch‐clamp approach is more sensitive than immunofluorescence since it allowed detecting ClC‐K1 in the CTAL and the intercalated cells at low frequency while ClC‐K1 was undetectable in Clcnk2‐/‐ mice using immunofluorescence.


Figure 12. Functional analysis of Clcnk2−/−mice. (A) Both furosemide (FURO, left‐hand panel), an inhibitor of NKCC2, and hydrochlorothiazide (HCTZ, right‐hand panel), a classical inhibitor of NCC, elicit significant natriuresis in Clcnk2+/+ mice while natriuresis is abolished (FURO) or dramatically blunted (HCTZ) in Clcnk2−/−mice. This experiment demonstrates the pivotal role of ClC‐K2 in the TAL and DCT. [Taken from Hennings et al. J Am Soc Nephrol 28: 209‐217, 2017. © 2017 The American Society of Nephrology, with permission. Ref. (156)]. (B) Elevated levels of prostaglandin E2 in Clcnk2−/−mice. Left‐hand panel: PGE2 is increased twofold in Clcnk2−/−mice as compared to WT. Right‐hand panel: the abundance of the inducible COX‐2 protein was highly augmented in the kidneys of Clcnk2−/−mice as compared to WT mice. [Taken from Grill et al. Acta Physiol (Oxf) 218: 198‐211, 2016. © 2016 publisher John Wiley and Sons, with permission. Ref. (141)].


Figure 13. Simplified scheme of NaCl absorption in the proximal tubule. The proximal tubule, first renal segment after the glomerulus, is involved in a plethora of transport processes that cannot be summarized in one cartoon. Here, we focus on the mechanisms implicated in NaCl transport. The transepithelial voltage (VTE) has a value of about −2 mV at the beginning of the segment (early proximal tubule) and reaches a value of about +2 mV in the second part of the proximal tubule (late proximal tubule). Transport systems also have a heterogeneous distribution in the two parts of the proximal tubule. Fundamentally, Na+ absorption at the apical side proceeds via a series of Na+‐coupled cotransporters and the Na+/H+ exchanger NHE3; at the basolateral side, Na+ exit to the interstitium proceeds via the Na+/K+‐ATPase and Na+‐HCO3cotransporter NBCE1. One part of Na+ is absorbed through the paracellular pathway in the second part of the proximal tubule. Cl can be absorbed through the paracellular pathway all along the entire length of the proximal tubule. Nevertheless, one base/Cl exchanger (CFEX) in the apical membrane may allow the entry of chloride into the cell. The exit at the basolateral membrane is not entirely defined but could include a K+‐Cl cotransporter and a Na+‐dependent Cl/HCO3 exchanger. To our knowledge, the molecular identity of these ion transporters has not been deciphered. KCC4 (gene: Slc12a7) has been suggested to underlie the K+‐Cl cotransporter. The Na+/H+ exchanger NHE3 is also of primary importance in the context of HCO3 absorption: within the cell, H+ and HCO3 are formed in the presence of carbonic anhydrase 2 following CO2 hydration in H2CO3; the protons exiting the cell via NHE3 combine with luminal HCO3 to form CO2 in the presence of membrane‐bound carbonic anhydrase 4 while cellular HCO3is taken in charge by the Na+‐HCO3 cotransporter NBCE1 on the basolateral side.


Figure 14. NaCl absorption along the TAL. Ion transport pathways for NaCl absorption in the TAL include: the Na+‐K+‐2Cl cotransporter NKCC2 (gene: Slc12a1), ROMK K+ channel (Kir1.1, gene: Kcnj1) in the apical membrane, Kir4.1/Kir5.1 K+ channels (genes: Kcnj10 and KcnjJ16), slo2.2 K+ channels (gene: Kcnt1) and ClC‐K1 and ClC‐K2 associated to barttin (Clcnk1, Clcnk2 and Bsnd) in the basolateral membrane. There is also another chloride channel called pseudo CFTR in the basolateral membrane that has not been molecularly identified. According to Feraille and Doucet (108), the α1β1 heterodimer is the most abundant Na+/K+‐ATPase along the renal tubule (genes: Atp1a1 and Atp1b1). The TAL is also involved in paracellular absorption of Mg2+ and Ca2+. Finally, let us mention that an additional K+ channel displaying an elementary conductance of 70 pS is present in the apical membrane. It has been proposed that ROMK participates to its formation because it is absent in Kcnj1 −/− mice (244,245).


Figure 15. NaCl absorption along the DCT. Ion transport pathways for NaCl transport in the DCT1 and DCT2 include: the Na+‐Cl cotransporter NCC (gene: Slc12a3), Kir4.1/Kir5.1 K+ channels (genes: Kcnj10 and KcnjJ16) and ClC‐K2/barttin (Clcnk2 and Bsnd). Additionally, the presence of a K+‐Cl cotransporter with unknown molecular identity in the basolateral membrane has been reported. The Na+/H+ exchanger NHE2 (gene: Slc9a2) and formate/Cl exchanger (molecular identity unknown) are more abundant in the DCT1 than in the DCT2; ENaC (formed by α, β and γ subunits; genes: Scnn1a, 1b and 1g, respectively) and Kir1.1 (R, gene: Kcnj1) are restricted to the DCT2. The DCT is also involved in transcellular absorption of Mg2+ (DCT1‐DCT2) and Ca2+ (DCT2) that are not illustrated here (257).


Figure 16. Modulation of the activity of the Na+‐Cl cotransport NCC by Kir4.1/Kir5.1 K+ channel. (A) Inhibition of Kir4.1 depolarizes plasma membrane and decreases the driving force for chloride across the membrane. As a consequence, chloride flux across ClC‐K2 is reduced, [Cl]i augments and the WNK/SPAK SYSTEM is inhibited. NCC activity is inhibited. (B) Stimulation of Kir4.1 hyperpolarizes plasma membrane and increases the driving force for chloride across the membrane. As a consequence, chloride flux across ClC‐K2 is higher, [Cl]i takes a lower value and the WNK4/SPAK SYSTEM is activated. NCC activity is stimulated. Dotted and solid lines represent a diminished and an enhanced function, respectively. Gray font means an inhibition or a decrease. Abbreviation: V, cell voltage; WNK, with‐no‐lysine kinase, SPAK, ste20‐proline‐alanine rich kinase. From Wang WH, Curr Opin Nephrol Hypertens 25: 429‐35, © Wolters Kluwer Health 2016, with permission [Ref. (437)].


Figure 17. NaCl transport across principal and type B intercalated cells in the CNT and CCD. In principal cells, simple arrangement of ion transport systems including Na+/K+‐ATPase and potassium channels (Kir4.1/Kir5.1 and additional K+ channels) in the basolateral membrane, and ENaC and ROMK (Kir1.1) channels in the apical membrane, allow Na+ absorption and K+ secretion, mainly under the control of aldosterone. The lumen‐negative transepithelial voltage generated by electrogenic Na+ absorption drives paracellular absorption of Cl. Type B intercalated cells (B‐IC) mediate NaCl absorption via a complex scheme involving apically located Cl/HCO3 exchanger pendrin (gene: Slc26a4) and Na+‐driven Cl/HCO3 exchanger NDCBE (gene: Slc4a8), and basolateral Na+‐HCO3 cotransporter AE4 (gene: Slc4a9) and ClC‐K2/barttin Cl channels. The absorption of NaCl in type B intercalated cells can only be observed in condition of low‐Na+ diet (high aldosterone). Type B intercalated cells can also secrete HCO3 into the lumen by the means of the apical Cl/HCO3 exchanger pendrin working in tandem with the V‐type H+‐ATPase and ClC‐K2/barttin Cl channels on the basolateral membrane. Type A intercalated cells secrete H+ into the lumen through the apical V‐type H+‐ATPase and H+/K+‐ATPase, which operate in tandem with the basolateral ClC‐K2/barttin Cl channel, the K+‐Cl cotransporter KCC4 (gene: Slc12a7) and the Cl/HCO3 exchangers AE1 (gene: Slc4a1). The H+/K+‐ATPase is also present in the OMCD. The SLC26A7 Cl/HCO3 exchanger (not shown here) is expressed across the basolateral membranes of the OMCD.


Figure 18. NaCl transport in type B intercalated cells is rather energized by vacuolar H+‐ATPase than Na+/K+‐ATPase. Transepithelial Na+ and Cl fluxes were measured on CCD segments isolated from mice fed a Na+‐depleted diet to evaluate the effects of amiloride (10−5 M, ENaC inhibitor), ouabain (10−4 M, Na+/K+‐ATPase inhibitor) and bafilomycin (4.10−8 M, V‐type H+‐ATPase inhibitor). (A) Na+ absorption is inhibited by ∼60% by either amiloride or ouabain. The effects are not additive indicating that the amiloride‐insensitive component is ouabain‐resistant. Cl absorption is not affected by amiloride or ouabain. (B) The amiloride‐insensitive Na+ and Cl fluxes are abolished in the presence bafilomycin. [With permission from Chambrey et al. Proc Natl Acad Sci U S A 110: 7928‐7933, 2013. © 2003 National Academy of Sciences. Ref. (63)].


Figure 19. Modeling ion transport in type B intercalated cells. The type B intercalated cells are endowed with a complex arrangement of ion transport systems allowing bicarbonate secretion and/or NaCl absorption. This figure shows the predicted effects of variations in basolateral membrane chloride conductance (gClC‐K) on net fluxes of Cl through ClC‐K2 (blue), of Na+ through NDCBE (red), and of apical HCO3 (black; left) and on net transcellular Na+, Cl, and HCO3 transport (right). The labels 1 to 3 correspond to relative gClC‐K values of 0, 0.15, and 1, respectively. [With permission from ©Pinelli et al. 2016, originally published in the Journal of General Physiology. https://doi:10.1085/jgp.201611623. Ref. (319)].
References
 1.Accardi A. Structure and gating of CLC channels and exchangers. J Physiol 593: 4129‐4138, 2015.
 2.Accardi A, Ferrera L, Pusch M. Drastic reduction of the slow gate of human muscle chloride channel (ClC‐1) by mutation C277S. J Physiol 534: 745‐752, 2001.
 3.Accardi A, Miller C. Secondary active transport mediated by a prokaryotic homologue of ClC Cl− channels. Nature 427: 803‐807, 2004.
 4.Accardi A, Pusch M. Fast and slow gating relaxations in the muscle chloride channel CLC‐1. J Gen Physiol 116: 433‐444, 2000.
 5.Adachi S, Uchida S, Ito H, Hata M, Hiroe M, Marumo F, Sasaki S. Two isoforms of a chloride channel predominantly expressed in thick ascending limb of Henle's loop and collecting ducts of rat kidney. J Biol Chem 269: 17677‐17683, 1994.
 6.Akizuki N, Uchida S, Sasaki S, Marumo F. Impaired solute accumulation in inner medulla of Clcnk1−/− mice kidney. Am J Physiol Renal Physiol 280: F79‐F87, 2001.
 7.Alpern RJ, Howlin KJ, Preisig PA. Active and passive components of chloride transport in the rat proximal convoluted tubule. J Clin Invest 76: 1360‐1366, 1985.
 8.Anagnostopoulos T. Anion permeation in the proximal tubule of Necturus kidney: The shunt pathway. J Membr Biol 24: 365‐380, 1975.
 9.Andrini O, Keck M, Briones R, Lourdel S, Vargas‐Poussou R, Teulon J. ClC‐K chloride channels: Emerging pathophysiology of Bartter syndrome type 3. Am J Physiol Renal Physiol 308: F1324‐F1334, 2015.
 10.Andrini O, Keck M, L'Hoste S, Briones R, Mansour‐Hendili L, Grand T, Sepulveda FV, Blanchard A, Lourdel S, Vargas‐Poussou R, Teulon J. CLCNKB mutations causing mild Bartter syndrome profoundly alter the pH and Ca dependence of ClC‐Kb channels. Pflugers Arch 466: 1713‐1723, 2014.
 11.Argenzio E, Moolenaar WH. Emerging biological roles of Cl− intracellular channel proteins. J Cell Sci 129: 4165‐4174, 2016.
 12.Arreola J, Begenisich T, Melvin JE. Conformation‐dependent regulation of inward rectifier chloride channel gating by extracellular protons. J Physiol 541: 103‐112, 2002.
 13.Arreola J, Park K, Melvin JE, Begenisich T. Three distinct chloride channels control anion movements in rat parotid acinar cells. J Physiol 490(Pt 2): 351‐362, 1996.
 14.Arroyo JP, Lagnaz D, Ronzaud C, Vazquez N, Ko BS, Moddes L, Ruffieux‐Daidie D, Hausel P, Koesters R, Yang B, Stokes JB, Hoover RS, Gamba G, Staub O. Nedd4‐2 modulates renal Na+‐Cl‐ cotransporter via the aldosterone‐SGK1‐Nedd4‐2 pathway. J Am Soc Nephrol 22: 1707‐1719, 2011.
 15.Bailey MA, Giebisch G, Abbiati T, Aronson PS, Gawenis LR, Shull GE, Wang T. NHE2‐mediated bicarbonate reabsorption in the distal tubule of NHE3 null mice. J Physiol 561: 765‐775, 2004.
 16.Balderas E, Ateaga‐Tlecuitl R, Rivera M, Gomora JC, Darszon A. Niflumic acid blocks native and recombinant T‐type channels. J Cell Physiol 227: 2542‐2555, 2012.
 17.Bandulik S, Schmidt K, Bockenhauer D, Zdebik AA, Humberg E, Kleta R, Warth R, Reichold M. The salt‐wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel. Pflugers Arch 461: 423‐435, 2011.
 18.Barajas L. Anatomy of the juxtaglomerular apparatus. Am J Physiol 237: F333‐F343, 1979.
 19.Barlassina C, Dal Fiume C, Lanzani C, Manunta P, Guffanti G, Ruello A, Bianchi G, Del Vecchio L, Macciardi F, Cusi D. Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt‐sensitive hypertension. Hum Mol Genet 16: 1630‐1638, 2007.
 20.Barone S, Amlal H, Xu J, Kujala M, Kere J, Petrovic S, Soleimani M. Differential regulation of basolateral Cl−/HCO3− exchangers SLC26A7 and AE1 in kidney outer medullary collecting duct. J Am Soc Nephrol 15: 2002‐2011, 2004.
 21.Barriere H, Belfodil R, Rubera I, Tauc M, Poujeol C, Bidet M, Poujeol P. CFTR null mutation altered cAMP‐sensitive and swelling‐activated Cl− currents in primary cultures of mouse nephron. Am J Physiol Renal Physiol 284: F796‐F811, 2003.
 22.Bartter FC, Pronove P, Gill JR, Jr., Maccardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. Am J Med 33: 811‐828, 1962.
 23.Bauer CK, Steinmeyer K, Schwarz JR, Jentsch TJ. Completely functional double‐barreled chloride channel expressed from a single Torpedo cDNA. Proc Natl Acad Sci U S A 88: 11052‐11056, 1991.
 24.Bazua‐Valenti S, Chavez‐Canales M, Rojas‐Vega L, Gonzalez‐Rodriguez X, Vazquez N, Rodriguez‐Gama A, Argaiz ER, Melo Z, Plata C, Ellison DH, Garcia‐Valdes J, Hadchouel J, Gamba G. The effect of WNK4 on the Na+‐Cl− cotransporter is modulated by intracellular chloride. J Am Soc Nephrol 26: 1781‐1786, 2015.
 25.Belfodil R, Barriere H, Rubera I, Tauc M, Poujeol C, Bidet M, Poujeol P. CFTR‐dependent and ‐independent swelling‐activated K+ currents in primary cultures of mouse nephron. Am J Physiol Renal Physiol 284: F812‐F828, 2003.
 26.Bell PD, Komlosi P, Zhang ZR. ATP as a mediator of macula densa cell signalling. Purinergic Signal 5: 461‐471, 2009.
 27.Bell PD, Lapointe JY, Cardinal J. Direct measurement of basolateral membrane potentials from cells of the macula densa. Am J Physiol 257: F463‐F468, 1989.
 28.Bell PD, Lapointe JY, Peti‐Peterdi J. Macula densa cell signaling. Annu Rev Physiol 65: 481‐500, 2003.
 29.Bell PD, Lapointe JY, Sabirov R, Hayashi S, Peti‐Peterdi J, Manabe K, Kovacs G, Okada Y. Macula densa cell signaling involves ATP release through a maxi anion channel. Proc Natl Acad Sci U S A 100: 4322‐4327, 2003.
 30.Bens M, Duong Van Huyen JP, Cluzeaud F, Teulon J, Vandewalle A. CFTR disruption impairs cAMP‐dependent Cl(−) secretion in primary cultures of mouse cortical collecting ducts. Am J Physiol Renal Physiol 281: F434‐F442, 2001.
 31.Bergler T, Stoelcker B, Jeblick R, Reinhold SW, Wolf K, Riegger GA, Kramer BK. High osmolality induces the kidney‐specific chloride channel CLC‐K1 by a serum and glucocorticoid‐inducible kinase 1 MAPK pathway. Kidney Int 74: 1170‐1177, 2008.
 32.Bertog M, Letz B, Kong W, Steinhoff M, Higgins MA, Bielfeld‐Ackermann A, Fromter E, Bunnett NW, Korbmacher C. Basolateral proteinase‐activated receptor (PAR‐2) induces chloride secretion in M‐1 mouse renal cortical collecting duct cells. J Physiol 521(Pt 1): 3‐17, 1999.
 33.Bidet M, Tauc M, Rubera I, de Renzis G, Poujeol C, Bohn MT, Poujeol P. Calcium‐activated chloride currents in primary cultures of rabbit distal convoluted tubule. Am J Physiol 271: F940‐F950, 1996.
 34.Birkenhager R, Otto E, Schurmann MJ, Vollmer M, Ruf EM, Maier‐Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, Hildebrandt F. Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. Nat Genet 29: 310‐314, 2001.
 35.Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hubner CA, Jentsch TJ. Leukoencephalopathy upon disruption of the chloride channel ClC‐2. J Neurosci 27: 6581‐6589, 2007.
 36.Boese SH, Glanville M, Aziz O, Gray MA, Simmons NL. Ca2+ and cAMP‐activated Cl‐ conductances mediate Cl‐ secretion in a mouse renal inner medullary collecting duct cell line. J Physiol 523(Pt 2): 325‐338, 2000.
 37.Boese SH, Glanville M, Gray MA, Simmons NL. The swelling‐activated anion conductance in the mouse renal inner medullary collecting duct cell line mIMCD‐K2. J Membr Biol 177: 51‐64, 2000.
 38.Boettger T, Hubner CA, Maier H, Rust MB, Beck FX, Jentsch TJ. Deafness and renal tubular acidosis in mice lacking the K‐Cl co‐transporter Kcc4. Nature 416: 874‐878, 2002.
 39.Bomsztyk K. Chloride transport by rat renal proximal tubule: Effects of bicarbonate absorption. Am J Physiol 250: F1046‐1054, 1986.
 40.Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, Davidoff MS, Holstein AF, Jentsch TJ. Male germ cells and photoreceptors, both dependent on close cell‐cell interactions, degenerate upon ClC‐2 Cl(−) channel disruption. EMBO J 20: 1289‐1299, 2001.
 41.Boucher RC, Cotton CU, Gatzy JT, Knowles MR, Yankaskas JR. Evidence for reduced Cl− and increased Na+ permeability in cystic fibrosis human primary cell cultures. J Physiol 405: 77‐103, 1988.
 42.Bouyer P, Paulais M, Cougnon M, Hulin P, Anagnostopoulos T, Planelles G. Extracellular ATP raises cytosolic calcium and activates basolateral chloride conductance in Necturus proximal tubule. J Physiol 510(Pt 2): 535‐548, 1998.
 43.Brands MW. Chronic blood pressure control. Compr Physiol 2: 2481‐2494, 2012.
 44.Brennan TM, Landau D, Shalev H, Lamb F, Schutte BC, Walder RY, Mark AL, Carmi R, Sheffield VC. Linkage of infantile Bartter syndrome with sensorineural deafness to chromosome 1p. Am J Hum Genet 62: 355‐361, 1998.
 45.Breton S, Marsolais M, Lapointe JY, Laprade R. Cell volume increases of physiologic amplitude activate basolateral K and CI conductances in the rabbit proximal convoluted tubule. J Am Soc Nephrol 7: 2072‐2087, 1996.
 46.Breton S, Marsolais M, Laprade R. Hypotonicity increases basolateral taurine permeability in rabbit proximal convoluted tubule. Am J Physiol 268: F595‐F603, 1995.
 47.Briggs JP, Schnermann JB. Whys and wherefores of juxtaglomerular apparatus function. Kidney Int 49: 1724‐1726, 1996.
 48.Brochard K, Boyer O, Blanchard A, Loirat C, Niaudet P, Macher MA, Deschenes G, Bensman A, Decramer S, Cochat P, Morin D, Broux F, Caillez M, Guyot C, Novo R, Jeunemaitre X, Vargas‐Poussou R. Phenotype‐genotype correlation in antenatal and neonatal variants of Bartter syndrome. Nephrol Dial Transplant 24: 1455‐1464, 2009.
 49.Brum S, Rueff J, Santos JR, Calado J. Unusual adult‐onset manifestation of an attenuated Bartter's syndrome type IV renal phenotype caused by a mutation in BSND. Nephrol Dial Transplant 22: 288‐289, 2007.
 50.Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R. X‐ray structure of a calcium‐activated TMEM16 lipid scramblase. Nature 516: 207‐212, 2014.
 51.Burg M, Grantham J, Abramow M, Orloff J. Preparation and study of fragments of single rabbit nephrons. Am J Physiol 210: 1293‐1298, 1966.
 52.Burg MB. Thick ascending limb of Henle's loop. Kidney Int 22: 454‐464, 1982.
 53.Bykova EA, Zhang XD, Chen TY, Zheng J. Large movement in the C terminus of CLC‐0 chloride channel during slow gating. Nat Struct Mol Biol 13: 1115‐1119, 2006.
 54.Cappola TP, Matkovich SJ, Wang W, van Booven D, Li M, Wang X, Qu L, Sweitzer NK, Fang JC, Reilly MP, Hakonarson H, Nerbonne JM, Dorn GW, 2nd. Loss‐of‐function DNA sequence variant in the CLCNKA chloride channel implicates the cardio‐renal axis in interindividual heart failure risk variation. Proc Natl Acad Sci U S A 108: 2456‐2461, 2011.
 55.Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra‐Moran O, Galietta LJ. TMEM16A, a membrane protein associated with calcium‐dependent chloride channel activity. Science 322: 590‐594, 2008.
 56.Cassola AC, Mollenhauer M, Fromter E. The intracellular chloride activity of rat kidney proximal tubular cells. Pflugers Arch 399: 259‐265, 1983.
 57.Castaneda‐Bueno M, Cervantes‐Perez LG, Vazquez N, Uribe N, Kantesaria S, Morla L, Bobadilla NA, Doucet A, Alessi DR, Gamba G. Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4‐dependent process. Proc Natl Acad Sci U S A 109: 7929‐7934, 2012.
 58.Castrop H. Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine. Acta Physiol (Oxf) 189: 3‐14, 2007.
 59.Castrop H, Schiessl IM. Physiology and pathophysiology of the renal Na‐K‐2Cl cotransporter (NKCC2). Am J Physiol Renal Physiol 307: F991‐F1002, 2014.
 60.Castrop H, Schnermann J. Isoforms of renal Na‐K‐2Cl cotransporter NKCC2: expression and functional significance. Am J Physiol Renal Physiol 295: F859‐F866, 2008.
 61.Catalan M, Niemeyer MI, Cid LP, Sepulveda FV. Basolateral ClC‐2 chloride channels in surface colon epithelium: Regulation by a direct effect of intracellular chloride. Gastroenterology 126: 1104‐1114, 2004.
 62.Catalan MA, Flores CA, Gonzalez‐Begne M, Zhang Y, Sepulveda FV, Melvin JE. Severe defects in absorptive ion transport in distal colons of mice that lack ClC‐2 channels. Gastroenterology 142: 346‐354, 2012.
 63.Chambrey R, Kurth I, Peti‐Peterdi J, Houillier P, Purkerson JM, Leviel F, Hentschke M, Zdebik AA, Schwartz GJ, Hubner CA, Eladari D. Renal intercalated cells are rather energized by a proton than a sodium pump. Proc Natl Acad Sci U S A 110: 7928‐7933, 2013.
 64.Chambrey R, Warnock DG, Podevin RA, Bruneval P, Mandet C, Belair MF, Bariety J, Paillard M. Immunolocalization of the Na+/H+ exchanger isoform NHE2 in rat kidney. Am J Physiol 275: F379‐F386, 1998.
 65.Chang PY, Zhang XG, Su XL. Lack of association of variants of the renal salt reabsorption‐related genes SLC12A3 and ClC‐Kb and hypertension in Mongolian and Han populations in Inner Mongolia. Genet Mol Res 10: 948‐954, 2011.
 66.Chen TY, Hwang TC. CLC‐0 and CFTR: Chloride channels evolved from transporters. Physiol Rev 88: 351‐387, 2008.
 67.Chen TY, Miller C. Nonequilibrium gating and voltage dependence of the ClC‐0 Cl‐ channel. J Gen Physiol 108: 237‐250, 1996.
 68.Cheng CJ, Lo YF, Chen JC, Huang CL, Lin SH. Functional severity of CLCNKB mutations correlates with phenotypes in patients with classic Bartter's syndrome. J Physiol 595: 5573‐5586, 2017.
 69.Cheng SH, Gregory RJ, Marshall J, Paul S, Souza DW, White GA, O'Riordan CR, Smith AE. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63: 827‐834, 1990.
 70.Chesnoy‐Marchais D. Characterization of a chloride conductance activated by hyperpolarization in Aplysia neurones. J Physiol 342: 277‐308, 1983.
 71.Chou CL, Knepper MA. In vitro perfusion of chinchilla thin limb segments: Segmentation and osmotic water permeability. Am J Physiol 263: F417‐F426, 1992.
 72.Chou CL, Knepper MA. In vitro perfusion of chinchilla thin limb segments: Urea and NaCl permeabilities. Am J Physiol 264: F337‐F343, 1993.
 73.Chou SY, Hsu KS, Otsu W, Hsu YC, Luo YC, Yeh C, Shehab SS, Chen J, Shieh V, He GA, Marean MB, Felsen D, Ding A, Poppas DP, Chuang JZ, Sung CH. CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer‐ and actin‐mediated endocytic trafficking. Nat Commun 7: 10412, 2016.
 74.Crawford I, Maloney PC, Zeitlin PL, Guggino WB, Hyde SC, Turley H, Gatter KC, Harris A, Higgins CF. Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proc Natl Acad Sci U S A 88: 9262‐9266, 1991.
 75.Cuevas CA, Su X‐T, Wang M‐X, Terker AS, Lin D‐H, McCormick JA, Yang C‐L, Ellison DH, Wang W‐H. Potassium Sensing by Renal Distal Tubules Requires Kir4.1. J Am Soc Nephrol 28: 1814‐1825, 2017.
 76.Curthoys NP, Moe OW. Proximal tubule function and response to acidosis. Clin J Am Soc Nephrol 9: 1627‐1638, 2014.
 77.Dang S, Feng S, Tien J, Peters CJ, Bulkley D, Lolicato M, Zhao J, Zuberbuhler K, Ye W, Qi L, Chen T, Craik CS, Jan YN, Minor DL, Jr., Cheng Y, Jan LY. Cryo‐EM structures of the TMEM16A calcium‐activated chloride channel. Nature 552: 426‐429, 2017.
 78.de la Fuente‐Ortega E, Gravotta D, Perez Bay A, Benedicto I, Carvajal‐Gonzalez JM, Lehmann GL, Lagos CF, Rodriguez‐Boulan E. Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP‐1. Mol Biol Cell 26: 1728‐1742, 2015.
 79.De Luca A, Tricarico D, Wagner R, Bryant SH, Tortorella V, Conte Camerino D. Opposite effects of enantiomers of clofibric acid derivative on rat skeletal muscle chloride conductance: Antagonism studies and theoretical modeling of two different receptor site interactions. J Pharmacol Exp Ther 260: 364‐368, 1992.
 80.Deneka D, Sawicka M, Lam AKM, Paulino C, Dutzler R. Structure of a volume‐regulated anion channel of the LRRC8 family. Nature 558: 254‐259, 2018.
 81.Denicourt N, Cai S, Garneau L, Brunette MG, Sauve R. Evidence from incorporation experiments for an anionic channel of small conductance at the apical membrane of the rabbit distal tubule. Biochim Biophys Acta 1285: 155‐166, 1996.
 82.Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, van Berkel C, Polder E, Tollard E, Darios F, Brice A, de Die‐Smulders CE, Vles JS, Vanderver A, Uziel G, Yalcinkaya C, Frints SG, Kalscheuer VM, Klooster J, Kamermans M, Abbink TE, Wolf NI, Sedel F, van der Knaap MS. Brain white matter oedema due to ClC‐2 chloride channel deficiency: An observational analytical study. Lancet Neurol 12: 659‐668, 2013.
 83.Devuyst O, Guggino WB. Chloride channels in the kidney: Lessons learned from knockout animals. Am J Physiol Renal Physiol 283: F1176‐1191, 2002.
 84.Devuyst O, Luciani A. Chloride transporters and receptor‐mediated endocytosis in the renal proximal tubule. J Physiol 593: 4151‐4164, 2015.
 85.Di Stefano A, Jounier S, Wittner M. Evidence supporting a role for KCl cotransporter in the thick ascending limb of Henle's loop. Kidney Int 60: 1809‐1823, 2001.
 86.Di Stefano A, Wittner M, Schlatter E, Lang HJ, Englert H, Greger R. Diphenylamine‐2‐carboxylate, a blocker of the Cl(−)‐conductive pathway in Cl(−)‐transporting epithelia. Pflugers Arch 405(Suppl 1): S95‐S100, 1985.
 87.Dimke H, Schnermann J. Axial and cellular heterogeneity in electrolyte transport pathways along the thick ascending limb. Acta Physiol (Oxf) 223: e13057, 2018.
 88.Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC. Cell‐specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone‐responsive epithelia from the rat: Localization by in situ hybridization and immunocytochemistry. J Cell Biol 127: 1907‐1921, 1994.
 89.Duffield M, Rychkov G, Bretag A, Roberts M. Involvement of helices at the dimer interface in ClC‐1 common gating. J Gen Physiol 121: 149‐161, 2003.
 90.Dutzler R, Campbell EB, Cadene M, Chait BT, MacKinnon R. X‐ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415: 287‐294, 2002.
 91.Dutzler R, Campbell EB, MacKinnon R. Gating the selectivity filter in ClC chloride channels. Science 300: 108‐112, 2003.
 92.Edelman A, Bouthier M, Anagnostopoulos T. Chloride distribution in the proximal convoluted tubule of Necturus kidney. J Membr Biol 62: 7‐17, 1981.
 93.Edwards JC. Chloride transport. Compr Physiol 2: 1061‐1092, 2012.
 94.El Khouri E, Toure A. Functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the SLC26 family of anion transporters (SLC26A8 and SLC26A9): physiological and pathophysiological relevance. Int J Biochem Cell Biol 52: 58‐67, 2014.
 95.Eladari D, Chambrey R, Picard N, Hadchouel J. Electroneutral absorption of NaCl by the aldosterone‐sensitive distal nephron: Implication for normal electrolytes homeostasis and blood pressure regulation. Cell Mol Life Sci 71: 2879‐2895, 2014.
 96.Ellison DH, Velazquez H, Wright FS. Thiazide‐sensitive sodium chloride cotransport in early distal tubule. Am J Physiol 253: F546‐F554, 1987.
 97.Embark HM, Bohmer C, Palmada M, Rajamanickam J, Wyatt AW, Wallisch S, Capasso G, Waldegger P, Seyberth HW, Waldegger S, Lang F. Regulation of CLC‐Ka/barttin by the ubiquitin ligase Nedd4‐2 and the serum‐ and glucocorticoid‐dependent kinases. Kidney Int 66: 1918‐1925, 2004.
 98.Estevez R, Boettger T, Stein V, Birkenhager R, Otto E, Hildebrandt F, Jentsch TJ. Barttin is a Cl− channel beta‐subunit crucial for renal Cl− reabsorption and inner ear K+ secretion. Nature 414: 558‐561, 2001.
 99.Estevez R, Pusch M, Ferrer‐Costa C, Orozco M, Jentsch TJ. Functional and structural conservation of CBS domains from CLC chloride channels. J Physiol 557: 363‐378, 2004.
 100.Estevez R, Schroeder BC, Accardi A, Jentsch TJ, Pusch M. Conservation of chloride channel structure revealed by an inhibitor binding site in ClC‐1. Neuron 38: 47‐59, 2003.
 101.Evans MG, Marty A. Calcium‐dependent chloride currents in isolated cells from rat lacrimal glands. J Physiol 378: 437‐460, 1986.
 102.Fahlke C, Fischer M. Physiology and pathophysiology of ClC‐K/barttin channels. Front Physiol 1: 3‐12, 2010.
 103.Fahlke C, Yu HT, Beck CL, Rhodes TH, George AL, Jr. Pore‐forming segments in voltage‐gated chloride channels. Nature 390: 529‐532, 1997.
 104.Faria D, Rock JR, Romao AM, Schweda F, Bandulik S, Witzgall R, Schlatter E, Heitzmann D, Pavenstadt H, Herrmann E, Kunzelmann K, Schreiber R. The calcium‐activated chloride channel Anoctamin 1 contributes to the regulation of renal function. Kidney Int 85: 1369‐1381, 2014.
 105.Fava C, Montagnana M, Almgren P, Rosberg L, Guidi GC, Berglund G, Melander O. The functional variant of the CLC‐Kb channel T481S is not associated with blood pressure or hypertension in Swedes. J Hypertens 25: 111‐116, 2007.
 106.Feng L, Campbell EB, Hsiung Y, MacKinnon R. Structure of a eukaryotic CLC transporter defines an intermediate state in the transport cycle. Science 330: 635‐641, 2010.
 107.Feraille E, Dizin E. Coordinated control of ENaC and Na+,K+‐ATPase in renal collecting duct. J Am Soc Nephrol 27: 2554‐2563, 2016.
 108.Feraille E, Doucet A. Sodium‐potassium‐adenosinetriphosphatase‐dependent sodium transport in the kidney: Hormonal control. Physiol Rev 81: 345‐418, 2001.
 109.Fernandes‐Rosa FL, Daniil G, Orozco IJ, Goppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, Schwarzmayr T, Strom TM, Jentsch TJ, Zennaro MC. A gain‐of‐function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet 50: 355‐361, 2018.
 110.Fischer M, Janssen AG, Fahlke C. Barttin activates ClC‐K channel function by modulating gating. J Am Soc Nephrol 21: 1281‐1289, 2010.
 111.Frindt G, Palmer LG. Effects of dietary K on cell‐surface expression of renal ion channels and transporters. Am J Physiol Renal Physiol 299: F890‐F897, 2010.
 112.Fritsch J, Edelman A. Modulation of the hyperpolarization‐activated Cl‐ current in human intestinal T84 epithelial cells by phosphorylation. J Physiol 490(Pt 1): 115‐128, 1996.
 113.Frizzell RA, Hanrahan JW. Physiology of epithelial chloride and fluid secretion. Cold Spring Harb Perspect Med 2: a009563, 2012.
 114.Frizzell RA, Rechkemmer G, Shoemaker RL. Altered regulation of airway epithelial cell chloride channels in cystic fibrosis. Science 233: 558‐560, 1986.
 115.Fromter E, Gessner K. Free‐flow potential profile along rat kidney proximal tubule. Pflugers Arch 351: 69‐83, 1974.
 116.Fromter E, Rumrich G, Ullrich KJ. Phenomenologic description of Na+, Cl− and HCO‐3 absorption from proximal tubules of rat kidney. Pflugers Arch 343: 189‐220, 1973.
 117.Fujita H, Hamazaki Y, Noda Y, Oshima M, Minato N. Claudin‐4 deficiency results in urothelial hyperplasia and lethal hydronephrosis. PLoS One 7: e52272, 2012.
 118.Furuya H, Breyer MD, Jacobson HR. Functional characterization of alpha‐ and beta‐intercalated cell types in rabbit cortical collecting duct. Am J Physiol 261: F377‐F385, 1991.
 119.Gamba G. Molecular physiology and pathophysiology of electroneutral cation‐chloride cotransporters. Physiol Rev 85: 423‐493, 2005.
 120.Gamba G. Regulation of the renal Na+‐Cl− cotransporter by phosphorylation and ubiquitylation. Am J Physiol Renal Physiol 303: F1573‐1583, 2012.
 121.Gamba G, Saltzberg SN, Lombardi M, Miyanoshita A, Lytton J, Hediger MA, Brenner BM, Hebert SC. Primary structure and functional expression of a cDNA encoding the thiazide‐sensitive, electroneutral sodium‐chloride cotransporter. Proc Natl Acad Sci U S A 90: 2749‐2753, 1993.
 122.Garcia‐Nieto V, Flores C, Luis‐Yanes MI, Gallego E, Villar J, Claverie‐Martin F. Mutation G47R in the BSND gene causes Bartter syndrome with deafness in two Spanish families. Pediatr Nephrol 21: 643‐648, 2006.
 123.Garcia Castano A, Perez de Nanclares G, Madariaga L, Aguirre M, Madrid A, Nadal I, Navarro M, Lucas E, Fijo J, Espino M, Espitaletta Z, Castano L, Ariceta G. Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm. PLoS One 8: e74673, 2013.
 124.Giebisch G. Renal potassium channels: Function, regulation, and structure. Kidney Int 60: 436‐445, 2001.
 125.Gong Y, Wang J, Yang J, Gonzales E, Perez R, Hou J. KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin‐8. Proc Natl Acad Sci U S A 112: 4340‐4345, 2015.
 126.Gong Y, Yu M, Yang J, Gonzales E, Perez R, Hou M, Tripathi P, Hering‐Smith KS, Hamm LL, Hou J. The Cap1‐claudin‐4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation. Proc Natl Acad Sci U S A 111: E3766‐F3774, 2014.
 127.Gradogna A, Babini E, Picollo A, Pusch M. A regulatory calcium‐binding site at the subunit interface of CLC‐K kidney chloride channels. J Gen Physiol 136: 311‐323, 2010.
 128.Gradogna A, Fenollar‐Ferrer C, Forrest LR, Pusch M. Dissecting a regulatory calcium‐binding site of CLC‐K kidney chloride channels. J Gen Physiol 140: 681‐696, 2012.
 129.Gradogna A, Imbrici P, Zifarelli G, Liantonio A, Camerino DC, Pusch M. I‐J loop involvement in the pharmacological profile of CLC‐K channels expressed in Xenopus oocytes. Biochim Biophys Acta 1838: 2745‐2756, 2014.
 130.Gradogna A, Pusch M. Alkaline pH block of CLC‐K kidney chloride channels mediated by a pore lysine residue. Biophys J 105: 80‐90, 2013.
 131.Gradogna A, Pusch M. Molecular pharmacology of kidney and inner ear CLC‐K chloride channels. Front Pharmacol 1: 130, 2010.
 132.Greger R. Cation selectivity of the isolated perfused cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch 390: 30‐37, 1981.
 133.Greger R. Ion transport mechanisms in thick ascending limb of Henle's loop of mammalian nephron. Physiol Rev 65: 760‐797, 1985.
 134.Greger R. Role of CFTR in the colon. Annu Rev Physiol 62: 467‐491, 2000.
 135.Greger R, Oberleithner H, Schlatter E, Cassola AC, Weidtke C. Chloride activity in cells of isolated perfused cortical thick ascending limbs of rabbit kidney. Pflugers Arch 399: 29‐34, 1983.
 136.Greger R, Schlatter E. Presence of luminal K+, a prerequisite for active NaCl transport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch 392: 92‐94, 1981.
 137.Greger R, Schlatter E. Cellular mechanism of the action of loop diuretics on the thick ascending limb of Henle's loop. Klin Wochenschr 61: 1019‐1027, 1983.
 138.Greger R, Schlatter E. Properties of the basolateral membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. A model for secondary active chloride transport. Pflugers Arch 396: 325‐334, 1983.
 139.Greger R, Schlatter E. Properties of the lumen membrane of the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch 396: 315‐324, 1983.
 140.Greger R, Schlatter E, Lang F. Evidence for electroneutral sodium chloride cotransport in the cortical thick ascending limb of Henle's loop of rabbit kidney. Pflugers Arch 396: 308‐314, 1983.
 141.Grill A, Schiessl IM, Gess B, Fremter K, Hammer A, Castrop H. Salt‐losing nephropathy in mice with a null mutation of the Clcnk2 gene. Acta Physiol (Oxf) 218: 198‐211, 2016.
 142.Grunder S, Thiemann A, Pusch M, Jentsch TJ. Regions involved in the opening of CIC‐2 chloride channel by voltage and cell volume. Nature 360: 759‐762, 1992.
 143.Guinamard R, Chraibi A, Teulon J. A small‐conductance Cl− channel in the mouse thick ascending limb that is activated by ATP and protein kinase A. J Physiol 485(Pt 1): 97‐112, 1995.
 144.Guinamard R, Paulais M, Teulon J. Inhibition of a small‐conductance cAMP‐dependent Cl− channel in the mouse thick ascending limb at low internal pH. J Physiol 490(Pt 3): 759‐765, 1996.
 145.Hadchouel J, Ellison DH, Gamba G. Regulation of renal electrolyte transport by WNK and SPAK‐OSR1 kinases. Annu Rev Physiol 78: 367‐389, 2016.
 146.Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ. Improved patch‐clamp techniques for high‐resolution current recording from cells and cell‐free membrane patches. Pflugers Arch 391: 85‐100, 1981.
 147.Hamilton KL, Devor DC. Basolateral membrane K+ channels in renal epithelial cells. Am J Physiol Renal Physiol 302: F1069‐1081, 2012.
 148.Hamilton KL, Moore AB. 50 Years of renal physiology from one man and the perfused tubule: Maurice B. Burg. Am J Physiol Renal Physiol 311: F291‐304, 2016.
 149.Hanaoka K, Devuyst O, Schwiebert EM, Wilson PD, Guggino WB. A role for CFTR in human autosomal dominant polycystic kidney disease. Am J Physiol 270: C389‐399, 1996.
 150.Hanke W, Miller C. Single chloride channels from Torpedo electroplax. Activation by protons. J Gen Physiol 82: 25‐45, 1983.
 151.Hayama A, Rai T, Sasaki S, Uchida S. Molecular mechanisms of Bartter syndrome caused by mutations in the BSND gene. Histochem Cell Biol 119: 485‐493, 2003.
 152.Hebert SC, Andreoli TE. Ionic conductance pathways in the mouse medullary thick ascending limb of Henle. The paracellular pathway and electrogenic Cl− absorption. J Gen Physiol 87: 567‐590, 1986.
 153.Hebert SC, Desir G, Giebisch G, Wang W. Molecular diversity and regulation of renal potassium channels. Physiol Rev 85: 319‐371, 2005.
 154.Heilberg IP, Totoli C, Calado JT. Adult presentation of Bartter syndrome type IV with erythrocytosis. Einstein (Sao Paulo) 13: 604‐606, 2015.
 155.Heinze C, Seniuk A, Sokolov MV, Huebner AK, Klementowicz AE, Szijarto IA, Schleifenbaum J, Vitzthum H, Gollasch M, Ehmke H, Schroeder BC, Hubner CA. Disruption of vascular Ca2+‐activated chloride currents lowers blood pressure. J Clin Invest 124: 675‐686, 2014.
 156.Hennings JC, Andrini O, Picard N, Paulais M, Hübner AK, Keck M, Cornière N, Böhm D, Jentsch TJ, Teulon J, Hübner CA, Eladari D. The ClC‐K2 chloride channel is critical for salt handling in the distal nephron. J Am Soc Nephrol 28: 209‐217, 2017.
 157.Hentschke M, Hentschke S, Borgmeyer U, Hubner CA, Kurth I. The murine AE4 promoter predominantly drives type B intercalated cell specific transcription. Histochem Cell Biol 132: 405‐412, 2009.
 158.Hibino H, Kurachi Y. Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology (Bethesda) 21: 336‐345, 2006.
 159.Hodgkin AL, Horowicz P. The influence of potassium and chloride ions on the membrane potential of single muscle fibres. J Physiol 148: 127‐160, 1959.
 160.Hoegg‐Beiler MB, Sirisi S, Orozco IJ, Ferrer I, Hohensee S, Auberson M, Godde K, Vilches C, de Heredia ML, Nunes V, Estevez R, Jentsch TJ. Disrupting MLC1 and GlialCAM and ClC‐2 interactions in leukodystrophy entails glial chloride channel dysfunction. Nat Commun 5: 3475, 2014.
 161.Holthofer H, Schulte BA, Pasternack G, Siegel GJ, Spicer SS. Three distinct cell populations in rat kidney collecting duct. Am J Physiol 253: C323‐328, 1987.
 162.Hou J, Renigunta A, Yang J, Waldegger S. Claudin‐4 forms paracellular chloride channel in the kidney and requires claudin‐8 for tight junction localization. Proc Natl Acad Sci U S A 107: 18010‐18015, 2010.
 163.Hunter M, Lopes AG, Boulpaep EL, Giebisch GH. Single channel recordings of calcium‐activated potassium channels in the apical membrane of rabbit cortical collecting tubules. Proc Natl Acad Sci U S A 81: 4237‐4239, 1984.
 164.Husted RF, Volk KA, Sigmund RD, Stokes JB. Anion secretion by the inner medullary collecting duct. Evidence for involvement of the cystic fibrosis transmembrane conductance regulator. J Clin Invest 95: 644‐650, 1995.
 165.Hwang TC, Lu L, Zeitlin PL, Gruenert DC, Huganir R, Guggino WB. Cl− channels in CF: Lack of activation by protein kinase C and cAMP‐dependent protein kinase. Science 244: 1351‐1353, 1989.
 166.Hwang TC, Yeh JT, Zhang J, Yu YC, Yeh HI, Destefano S. Structural mechanisms of CFTR function and dysfunction. J Gen Physiol 150: 539‐570, 2018.
 167.Imai M, Yoshitomi K. Electrophysiological study of inner medullary collecting duct of hamsters. Pflugers Arch 416: 180‐188, 1990.
 168.Imbrici P, Altamura C, Pessia M, Mantegazza R, Desaphy JF, Camerino DC. ClC‐1 chloride channels: State‐of‐the‐art research and future challenges. Front Cell Neurosci 9: 156, 2015.
 169.Imbrici P, Liantonio A, Gradogna A, Pusch M, Camerino DC. Targeting kidney CLC‐K channels: Pharmacological profile in a human cell line versus Xenopus oocytes. Biochim Biophys Acta 1838: 2484‐2491, 2014.
 170.Imbrici P, Tricarico D, Mangiatordi GF, Nicolotti O, Lograno MD, Conte D, Liantonio A. Pharmacovigilance database search discloses ClC‐K channels as a novel target of the AT1 receptor blockers valsartan and olmesartan. Br J Pharmacol 174: 1972‐1983, 2017.
 171.Ishibashi K, Sasaki S, Yoshiyama N. Intracellular chloride activity of rabbit proximal straight tubule perfused in vitro. Am J Physiol 255: F49‐F56, 1988.
 172.Isozaki T, Yoshitomi K, Imai M. Effects of Cl− transport inhibitors on Cl− permeability across hamster ascending thin limb. Am J Physiol 257: F92‐F98, 1989.
 173.Jacques T, Picard N, Miller RL, Riemondy KA, Houillier P, Sohet F, Ramakrishnan SK, Busst CJ, Jayat M, Corniere N, Hassan H, Aronson PS, Hennings JC, Hubner CA, Nelson RD, Chambrey R, Eladari D. Overexpression of pendrin in intercalated cells produces chloride‐sensitive hypertension. J Am Soc Nephrol 24: 1104‐1113, 2013.
 174.Janssen AG, Scholl U, Domeyer C, Nothmann D, Leinenweber A, Fahlke C. Disease‐causing dysfunctions of barttin in Bartter syndrome type IV. J Am Soc Nephrol 20: 145‐153, 2009.
 175.Jeck N, Konrad M, Peters M, Weber S, Bonzel KE, Seyberth HW. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter‐Gitelman phenotype. Pediatr Res 48: 754‐758, 2000.
 176.Jeck N, Waldegger P, Doroszewicz J, Seyberth H, Waldegger S. A common sequence variation of the CLCNKB gene strongly activates ClC‐Kb chloride channel activity. Kidney Int 65: 190‐197, 2004.
 177.Jeck N, Waldegger S, Lampert A, Boehmer C, Waldegger P, Lang PA, Wissinger B, Friedrich B, Risler T, Moehle R, Lang UE, Zill P, Bondy B, Schaeffeler E, Asante‐Poku S, Seyberth H, Schwab M, Lang F. Activating mutation of the renal epithelial chloride channel ClC‐Kb predisposing to hypertension. Hypertension 43: 1175‐1181, 2004.
 178.Jentsch TJ. CLC chloride channels and transporters: From genes to protein structure, pathology and physiology. Crit Rev Biochem Mol Biol 43: 3‐36, 2008.
 179.Jentsch TJ. Discovery of CLC transport proteins: Cloning, structure, function and pathophysiology. J Physiol 593: 4091‐4109, 2015.
 180.Jentsch TJ. VRACs and other ion channels and transporters in the regulation of cell volume and beyond. Nat Rev Mol Cell Biol 17: 293‐307, 2016.
 181.Jentsch TJ, Gunther W, Pusch M, Schwappach B. Properties of voltage‐gated chloride channels of the ClC gene family. J Physiol 482: 19S‐25S, 1995.
 182.Jentsch TJ, Lutter D, Planells‐Cases R, Ullrich F, Voss FK. VRAC: Molecular identification as LRRC8 heteromers with differential functions. Pflugers Arch 468: 385‐393, 2016.
 183.Jentsch TJ, Pusch M. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease. Physiol Rev 98: 1493‐1590, 2018.
 184.Jentsch TJ, Stein V, Weinreich F, Zdebik AA. Molecular structure and physiological function of chloride channels. Physiol Rev 82: 503‐568, 2002.
 185.Jentsch TJ, Steinmeyer K, Schwarz G. Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348: 510‐514, 1990.
 186.Jeworutzki E, Lopez‐Hernandez T, Capdevila‐Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Muller CS, Schulte U, Nunes V, Martinez A, Jentsch TJ, Gasull X, Pusch M, Estevez R. GlialCAM, a protein defective in a leukodystrophy, serves as a ClC‐2 Cl(−) channel auxiliary subunit. Neuron 73: 951‐961, 2012.
 187.Jordt SE, Jentsch TJ. Molecular dissection of gating in the ClC‐2 chloride channel. EMBO J 16: 1582‐1592, 1997.
 188.Jouret F, Bernard A, Hermans C, Dom G, Terryn S, Leal T, Lebecque P, Cassiman JJ, Scholte BJ, de Jonge HR, Courtoy PJ, Devuyst O. Cystic fibrosis is associated with a defect in apical receptor‐mediated endocytosis in mouse and human kidney. J Am Soc Nephrol 18: 707‐718, 2007.
 189.Jouret F, Devuyst O. CFTR and defective endocytosis: New insights in the renal phenotype of cystic fibrosis. Pflugers Arch 457: 1227‐1236, 2009.
 190.Kaissling B, Kriz W. Structural analysis of the rabbit kidney. Adv Anat Embryol Cell Biol 56: 1‐123, 1979.
 191.Kaissling B, Le Hir M. Distal tubular segments of the rabbit kidney after adaptation to altered Na‐ and K‐intake. I. Structural changes. Cell Tissue Res 224: 469‐492, 1982.
 192.Karniski LP, Aronson PS. Anion exchange pathways for Cl− transport in rabbit renal microvillus membranes. Am J Physiol 253: F513‐F521, 1987.
 193.Karniski LP, Aronson PS. Chloride/formate exchange with formic acid recycling: A mechanism of active chloride transport across epithelial membranes. Proc Natl Acad Sci U S A 82: 6362‐6365, 1985.
 194.Kashgarian M, Biemesderfer D, Caplan M, Forbush B, 3rd. Monoclonal antibody to Na,K‐ATPase: Immunocytochemical localization along nephron segments. Kidney Int 28: 899‐913, 1985.
 195.Katz AI, Doucet A, Morel F. Na‐K‐ATPase activity along the rabbit, rat, and mouse nephron. Am J Physiol 237: F114‐F120, 1979.
 196.Keck M, Andrini O, Lahuna O, Burgos J, Cid LP, Sepulveda FV, L'Hoste S, Blanchard A, Vargas‐Poussou R, Lourdel S, Teulon J. Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression. Hum Mutat 34: 1269‐1278, 2013.
 197.Kibble JD, Balloch KJ, Neal AM, Hill C, White S, Robson L, Green R, Taylor CJ. Renal proximal tubule function is preserved in Cftr(tm2cam) deltaF508 cystic fibrosis mice. J Physiol 532: 449‐457, 2001.
 198.Kibble JD, Neal A, Green R, Colledge WH, Taylor CJ. Effect of acute saline volume expansion in the anaesthetised DeltaF508 cystic fibrosis mouse. Pflugers Arch 443(Suppl 1): S17‐21, 2001.
 199.Kibble JD, Neal AM, Colledge WH, Green R, Taylor CJ. Evidence for cystic fibrosis transmembrane conductance regulator‐dependent sodium reabsorption in kidney, using Cftr(tm2cam) mice. J Physiol 526(Pt 1): 27‐34, 2000.
 200.Kieferle S, Fong P, Bens M, Vandewalle A, Jentsch TJ. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proc Natl Acad Sci U S A 91: 6943‐6947, 1994.
 201.Kim J, Kim YH, Cha JH, Tisher CC, Madsen KM. Intercalated cell subtypes in connecting tubule and cortical collecting duct of rat and mouse. J Am Soc Nephrol 10: 1‐12, 1999.
 202.Kobayashi K, Uchida S, Mizutani S, Sasaki S, Marumo F. Intrarenal and cellular localization of CLC‐K2 protein in the mouse kidney. J Am Soc Nephrol 12: 1327‐1334, 2001.
 203.Kokko JP. Sodium chloride and water transport in the descending limb of Henle. J Clin Invest 49: 1838‐1846, 1970.
 204.Komhoff M, Laghmani K. Pathophysiology of antenatal Bartter's syndrome. Curr Opin Nephrol Hypertens 26: 419‐425, 2017.
 205.Komlosi P, Fintha A, Bell PD. Current mechanisms of macula densa cell signalling. Acta Physiol Scand 181: 463‐469, 2004.
 206.Kondo Y, Abe K, Igarashi Y, Kudo K, Tada K, Yoshinaga K. Direct evidence for the absence of active Na+ reabsorption in hamster ascending thin limb of Henle's loop. J Clin Invest 91: 5‐11, 1993.
 207.Kondo Y, Yoshitomi K, Imai M. Effect of pH on Cl− transport in TAL of Henle's loop. Am J Physiol 253: F1216‐F1222, 1987.
 208.Kondo Y, Yoshitomi K, Imai M. Effects of anion transport inhibitors and ion substitution on Cl− transport in TAL of Henle's loop. Am J Physiol 253: F1206‐F1215, 1987.
 209.Konrad M, Vollmer M, Lemmink HH, van den Heuvel LP, Jeck N, Vargas‐Poussou R, Lakings A, Ruf R, Deschenes G, Antignac C, Guay‐Woodford L, Knoers NV, Seyberth HW, Feldmann D, Hildebrandt F. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 11: 1449‐1459, 2000.
 210.Koster AK, Wood CAP, Thomas‐Tran R, Chavan TS, Almqvist J, Choi KH, Du Bois J, Maduke M. A selective class of inhibitors for the CLC‐Ka chloride ion channel. Proc Natl Acad Sci U S A 115: E4900‐E4909, 2018.
 211.Koulouridis E, Koulouridis I. Molecular pathophysiology of Bartter's and Gitelman's syndromes. World J Pediatr 11: 113‐125, 2015.
 212.Kriz W, Bankir L. A standard nomenclature for structures of the kidney. The Renal Commission of the International Union of Physiological Sciences (IUPS). Kidney Int 33: 1‐7, 1988.
 213.Kunau RT, Jr., Weller DR, Webb HL. Clarification of the site of action of chlorothiazide in the rat nephron. J Clin Invest 56: 401‐407, 1975.
 214.Kunzelmann K, Schreiber R, Nitschke R, Mall M. Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Arch 440: 193‐201, 2000.
 215.L'Hoste S, Diakov A, Andrini O, Genete M, Pinelli L, Grand T, Keck M, Paulais M, Beck L, Korbmacher C, Teulon J, Lourdel S. Characterization of the mouse ClC‐K1/barttin chloride channel. Biochim Biophys Acta 1828: 2399‐2409, 2013.
 216.Lachheb S, Cluzeaud F, Bens M, Genete M, Hibino H, Lourdel S, Kurachi Y, Vandewalle A, Teulon J, Paulais M. Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells. Am J Physiol Renal Physiol 294: F1398‐F1407, 2008.
 217.Lansdell KA, Delaney SJ, Lunn DP, Thomson SA, Sheppard DN, Wainwright BJ. Comparison of the gating behaviour of human and murine cystic fibrosis transmembrane conductance regulator Cl− channels expressed in mammalian cells. J Physiol 508(Pt 2): 379‐392, 1998.
 218.Lapointe JY, Laamarti A, Hurst AM, Fowler BC, Bell PD. Activation of Na:2Cl:K cotransport by luminal chloride in macula densa cells. Kidney Int 47: 752‐757, 1995.
 219.Le Moellic C, Boulkroun S, Gonzalez‐Nunez D, Dublineau I, Cluzeaud F, Fay M, Blot‐Chabaud M, Farman N. Aldosterone and tight junctions: Modulation of claudin‐4 phosphorylation in renal collecting duct cells. Am J Physiol Cell Physiol 289: C1513‐C1521, 2005.
 220.Lee BH, Cho HY, Lee H, Han KH, Kang HG, Ha IS, Lee JH, Park YS, Shin JI, Lee DY, Kim SY, Choi Y, Cheong HI. Genetic basis of Bartter syndrome in Korea. Nephrol Dial Transplant 27: 1516‐1521, 2012.
 221.Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T. ClC‐7 is a slowly voltage‐gated 2Cl(−)/1H(+)‐exchanger and requires Ostm1 for transport activity. EMBO J 30: 2140‐2152, 2011.
 222.Lerma J, Martin del Rio R. Chloride transport blockers prevent N‐methyl‐D‐aspartate receptor‐channel complex activation. Mol Pharmacol 41: 217‐222, 1992.
 223.Letz B, Korbmacher C. cAMP stimulates CFTR‐like Cl− channels and inhibits amiloride‐sensitive Na+ channels in mouse CCD cells. Am J Physiol 272: C657‐C666, 1997.
 224.Leviel F, Hubner CA, Houillier P, Morla L, El Moghrabi S, Brideau G, Hassan H, Parker MD, Kurth I, Kougioumtzes A, Sinning A, Pech V, Riemondy KA, Miller RL, Hummler E, Shull GE, Aronson PS, Doucet A, Wall SM, Chambrey R, Eladari D. The Na+‐dependent chloride‐bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice. J Clin Invest 120: 1627‐1635, 2010.
 225.Liantonio A, Accardi A, Carbonara G, Fracchiolla G, Loiodice F, Tortorella P, Traverso S, Guida P, Pierno S, De Luca A, Camerino DC, Pusch M. Molecular requisites for drug binding to muscle CLC‐1 and renal CLC‐K channel revealed by the use of phenoxy‐alkyl derivatives of 2‐(p‐chlorophenoxy)propionic acid. Mol Pharmacol 62: 265‐271, 2002.
 226.Liantonio A, Gramegna G, Camerino GM, Dinardo MM, Scaramuzzi A, Potenza MA, Montagnani M, Procino G, Lasorsa DR, Mastrofrancesco L, Laghezza A, Fracchiolla G, Loiodice F, Perrone MG, Lopedota A, Conte S, Penza R, Valenti G, Svelto M, Camerino DC. In‐vivo administration of CLC‐K kidney chloride channels inhibitors increases water diuresis in rats: A new drug target for hypertension? J Hypertens 30: 153‐167, 2012.
 227.Liantonio A, Imbrici P, Camerino GM, Fracchiolla G, Carbonara G, Giannico D, Gradogna A, Mangiatordi GF, Nicolotti O, Tricarico D, Pusch M, Camerino DC. Kidney CLC‐K chloride channels inhibitors: Structure‐based studies and efficacy in hypertension and associated CLC‐K polymorphisms. J Hypertens 34: 981‐992, 2016.
 228.Liantonio A, Picollo A, Babini E, Carbonara G, Fracchiolla G, Loiodice F, Tortorella V, Pusch M, Camerino DC. Activation and inhibition of kidney CLC‐K chloride channels by fenamates. Mol Pharmacol 69: 165‐173, 2006.
 229.Liantonio A, Picollo A, Carbonara G, Fracchiolla G, Tortorella P, Loiodice F, Laghezza A, Babini E, Zifarelli G, Pusch M, Camerino DC. Molecular switch for CLC‐K Cl− channel block/activation: Optimal pharmacophoric requirements towards high‐affinity ligands. Proc Natl Acad Sci U S A 105: 1369‐1373, 2008.
 230.Liantonio A, Pusch M, Picollo A, Guida P, De Luca A, Pierno S, Fracchiolla G, Loiodice F, Tortorella P, Conte Camerino D. Investigations of pharmacologic properties of the renal CLC‐K1 chloride channel co‐expressed with barttin by the use of 2‐(p‐Chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride channels blockers. J Am Soc Nephrol 15: 13‐20, 2004.
 231.Lin RC, Morris BJ. Polymorphism (1339G>A; A447T) in exon 13 of human kidney chloride channel gene CLCNKA. Hum Mutat 16: 96, 2000.
 232.Lin YW, Lin CW, Chen TY. Elimination of the slow gating of ClC‐0 chloride channel by a point mutation. J Gen Physiol 114: 1‐12, 1999.
 233.Lisal J, Maduke M. The ClC‐0 chloride channel is a ‘broken’ Cl−/H+ antiporter. Nat Struct Mol Biol 15: 805‐810, 2008.
 234.Liu W, Morimoto T, Kondo Y, Iinuma K, Uchida S, Sasaki S, Marumo F, Imai M. Analysis of NaCl transport in thin ascending limb of Henle's loop in CLC‐K1 null mice. Am J Physiol Renal Physiol 282: F451‐F457, 2002.
 235.Loffing J, Loffing‐Cueni D, Macher A, Hebert SC, Olson B, Knepper MA, Rossier BC, Kaissling B. Localization of epithelial sodium channel and aquaporin‐2 in rabbit kidney cortex. Am J Physiol Renal Physiol 278: F530‐539, 2000.
 236.Loffing J, Loffing‐Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JG, Bindels RJ, Kaissling B. Distribution of transcellular calcium and sodium transport pathways along mouse distal nephron. Am J Physiol Renal Physiol 281: F1021‐F1027, 2001.
 237.Lorenz C, Pusch M, Jentsch TJ. Heteromultimeric CLC chloride channels with novel properties. Proc Natl Acad Sci U S A 93: 13362‐13366, 1996.
 238.Lorenz JN, Baird NR, Judd LM, Noonan WT, Andringa A, Doetschman T, Manning PA, Liu LH, Miller ML, Shull GE. Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome. J Biol Chem 277: 37871‐37880, 2002.
 239.Louet M, Bitam S, Bakouh N, Bignon Y, Planelles G, Lagorce D, Miteva MA, Eladari D, Teulon J, Villoutreix BO. In silico model of the human ClC‐Kb chloride channel: Pore mapping, biostructural pathology and drug screening. Sci Rep 7: 7249, 2017.
 240.Lourdel S, Paulais M, Cluzeaud F, Bens M, Tanemoto M, Kurachi Y, Vandewalle A, Teulon J. An inward rectifier K(+) channel at the basolateral membrane of the mouse distal convoluted tubule: Similarities with Kir4‐Kir5.1 heteromeric channels. J Physiol 538: 391‐404, 2002.
 241.Lourdel S, Paulais M, Marvao P, Nissant A, Teulon J. A chloride channel at the basolateral membrane of the distal‐convoluted tubule: A candidate ClC‐K channel. J Gen Physiol 121: 287‐300, 2003.
 242.Lu M, Dong K, Egan ME, Giebisch GH, Boulpaep EL, Hebert SC. Mouse cystic fibrosis transmembrane conductance regulator forms cAMP‐PKA‐regulated apical chloride channels in cortical collecting duct. Proc Natl Acad Sci U S A 107: 6082‐6087, 2010.
 243.Lu M, Leng Q, Egan ME, Caplan MJ, Boulpaep EL, Giebisch GH, Hebert SC. CFTR is required for PKA‐regulated ATP sensitivity of Kir1.1 potassium channels in mouse kidney. J Clin Invest 116: 797‐807, 2006.
 244.Lu M, Wang T, Yan Q, Wang W, Giebisch G, Hebert SC. ROMK is required for expression of the 70‐pS K channel in the thick ascending limb. Am J Physiol Renal Physiol 286: F490‐F495, 2004.
 245.Lu M, Wang T, Yan Q, Yang X, Dong K, Knepper MA, Wang W, Giebisch G, Shull GE, Hebert SC. Absence of small conductance K+ channel (SK) activity in apical membranes of thick ascending limb and cortical collecting duct in ROMK (Bartter's) knockout mice. J Biol Chem 277: 37881‐37887, 2002.
 246.Ma K, Wang H, Yu J, Wei M, Xiao Q. New insights on the regulation of Ca(2+)‐activated chloride channel TMEM16A. J Cell Physiol 232: 707‐716, 2017.
 247.Macri P, Breton S, Beck JS, Cardinal J, Laprade R. Basolateral K+, Cl−, and HCO3− conductances and cell volume regulation in rabbit PCT. Am J Physiol 264: F365‐F376, 1993.
 248.Madsen KM, Tisher CC. Structural‐functional relationship along the distal nephron. Am J Physiol 250: F1‐15, 1986.
 249.Malvezzi M, Chalat M, Janjusevic R, Picollo A, Terashima H, Menon AK, Accardi A. Ca2+‐dependent phospholipid scrambling by a reconstituted TMEM16 ion channel. Nat Commun 4: 2367, 2013.
 250.Marunaka Y, Eaton DC. Chloride channels in the apical membrane of a distal nephron A6 cell line. Am J Physiol 258: C352‐368, 1990.
 251.Marunaka Y, Eaton DC. Effects of insulin and phosphatase on a Ca2(+)‐dependent Cl− channel in a distal nephron cell line (A6). J Gen Physiol 95: 773‐789, 1990.
 252.Marvao P, De Jesus Ferreira MC, Bailly C, Paulais M, Bens M, Guinamard R, Moreau R, Vandewalle A, Teulon J. Cl− absorption across the thick ascending limb is not altered in cystic fibrosis mice. A role for a pseudo‐CFTR Cl− channel. J Clin Invest 102: 1986‐1993, 1998.
 253.Matsumura Y, Uchida S, Kondo Y, Miyazaki H, Ko SB, Hayama A, Morimoto T, Liu W, Arisawa M, Sasaki S, Marumo F. Overt nephrogenic diabetes insipidus in mice lacking the CLC‐K1 chloride channel. Nat Genet 21: 95‐98, 1999.
 254.Matulef K, Howery AE, Tan L, Kobertz WR, Du Bois J, Maduke M. Discovery of potent CLC chloride channel inhibitors. ACS Chem Biol 3: 419‐428, 2008.
 255.Mayan H, Vered I, Mouallem M, Tzadok‐Witkon M, Pauzner R, Farfel Z. Pseudohypoaldosteronism type II: Marked sensitivity to thiazides, hypercalciuria, normomagnesemia, and low bone mineral density. J Clin Endocrinol Metab 87: 3248‐3254, 2002.
 256.McCallum L, Lip S, Padmanabhan S. The hidden hand of chloride in hypertension. Pflugers Arch 467: 595‐603, 2015.
 257.McCormick JA, Ellison DH. Distal convoluted tubule. Compr Physiol 5: 45‐98, 2015.
 258.Meyer K, Korbmacher C. Cell swelling activates ATP‐dependent voltage‐gated chloride channels in M‐1 mouse cortical collecting duct cells. J Gen Physiol 108: 177‐193, 1996.
 259.Miller C. Open‐state substructure of single chloride channels from Torpedo electroplax. Philos Trans R Soc Lond B Biol Sci 299: 401‐411, 1982.
 260.Miller C. ClC chloride channels viewed through a transporter lens. Nature 440: 484‐489, 2006.
 261.Miller C. In the beginning: A personal reminiscence on the origin and legacy of ClC‐0, the ‘Torpedo Cl(−) channel’. J Physiol 593: 4085‐4090, 2015.
 262.Miller C, White MM. A voltage‐dependent chloride conductance channel from Torpedo electroplax membrane. Ann N Y Acad Sci 341: 534‐551, 1980.
 263.Miller C, White MM. Dimeric structure of single chloride channels from Torpedo electroplax. Proc Natl Acad Sci U S A 81: 2772‐2775, 1984.
 264.Miyamura N, Matsumoto K, Taguchi T, Tokunaga H, Nishikawa T, Nishida K, Toyonaga T, Sakakida M, Araki E. Atypical Bartter syndrome with sensorineural deafness with G47R mutation of the beta‐subunit for ClC‐Ka and ClC‐Kb chloride channels, barttin. J Clin Endocrinol Metab 88: 781‐786, 2003.
 265.Molony DA, Reeves WB, Andreoli TE. Na+:K+:2Cl− cotransport and the thick ascending limb. Kidney Int 36: 418‐426, 1989.
 266.Mongin AA. Volume‐regulated anion channel–a frenemy within the brain. Pflugers Arch 468: 421‐441, 2016.
 267.Monroy A, Plata C, Hebert SC, Gamba G. Characterization of the thiazide‐sensitive Na(+)‐Cl(−) cotransporter: A new model for ions and diuretics interaction. Am J Physiol Renal Physiol 279: F161‐F169, 2000.
 268.Mount DB. Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol 9: 1974‐1986, 2014.
 269.Murthy M, Kurz T, O'Shaughnessy KM. WNK signalling pathways in blood pressure regulation. Cell Mol Life Sci 74: 1261‐1280, 2017.
 270.Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, Furuse K, Sasaki H, Fujimura A, Imai M, Kusano E, Tsukita S, Furuse M. Claudin‐2‐deficient mice are defective in the leaky and cation‐selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci U S A 107: 8011‐8016, 2010.
 271.Muto S, Yasoshima K, Yoshitomi K, Imai M, Asano Y. Electrophysiological identification of alpha‐ and beta‐intercalated cells and their distribution along the rabbit distal nephron segments. J Clin Invest 86: 1829‐1839, 1990.
 272.Nazareth D, Walshaw M. A review of renal disease in cystic fibrosis. J Cyst Fibros 12: 309‐317, 2013.
 273.Nesterov V, Dahlmann A, Krueger B, Bertog M, Loffing J, Korbmacher C. Aldosterone‐dependent and ‐independent regulation of the epithelial sodium channel (ENaC) in mouse distal nephron. Am J Physiol Renal Physiol 303: F1289‐F1299, 2012.
 274.Niemeyer MI, Cid LP, Sepulveda FV, Blanz J, Auberson M, Jentsch TJ. No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 42: 3, 2010.
 275.Niemeyer MI, Cid LP, Yusef YR, Briones R, Sepulveda FV. Voltage‐dependent and ‐independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons. J Physiol 587: 1387‐1400, 2009.
 276.Niemeyer MI, Cid LP, Zuniga L, Catalan M, Sepulveda FV. A conserved pore‐lining glutamate as a voltage‐ and chloride‐dependent gate in the ClC‐2 chloride channel. J Physiol 553: 873‐879, 2003.
 277.Niemeyer MI, Yusef YR, Cornejo I, Flores CA, Sepulveda FV, Cid LP. Functional evaluation of human ClC‐2 chloride channel mutations associated with idiopathic generalized epilepsies. Physiol Genomics 19: 74‐83, 2004.
 278.Nilius B, Droogmans G. Amazing chloride channels: An overview. Acta Physiol Scand 177: 119‐147, 2003.
 279.Nissant A, Lourdel S, Baillet S, Paulais M, Marvao P, Teulon J, Imbert‐Teboul M. Heterogeneous distribution of chloride channels along the distal convoluted tubule probed by single‐cell RT‐PCR and patch clamp. Am J Physiol Renal Physiol 287: F1233‐F1243, 2004.
 280.Nissant A, Paulais M, Lachheb S, Lourdel S, Teulon J. Similar chloride channels in the connecting tubule and cortical collecting duct of the mouse kidney. Am J Physiol Renal Physiol 290: F1421‐F1429, 2006.
 281.Nomura N, Kamiya K, Ikeda K, Yui N, Chiga M, Sohara E, Rai T, Sakaki S, Uchida S. Treatment with 17‐allylamino‐17‐demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type IV caused by mutated Bsnd in mice. Biochem Biophys Res Commun 441: 544‐549, 2013.
 282.Nomura N, Shoda W, Wang Y, Mandai S, Furusho T, Takahashi D, Zeniya M, Sohara E, Rai T, Uchida S. Role of ClC‐K and barttin in low potassium‐induced sodium chloride cotransporter activation and hypertension in mouse kidney. Biosci Rep 38: pii: BSR20171243, 2018.
 283.Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, Jentsch TJ, Sasaki S, Uchida S. Generation and analyses of R8L barttin knockin mouse. Am J Physiol Renal Physiol 301: F297‐F307, 2011.
 284.Nozu K, Fu XJ, Nakanishi K, Yoshikawa N, Kaito H, Kanda K, Krol RP, Miyashita R, Kamitsuji H, Kanda S, Hayashi Y, Satomura K, Shimizu N, Iijima K, Matsuo M. Molecular analysis of patients with type III Bartter syndrome: Picking up large heterozygous deletions with semiquantitative PCR. Pediatr Res 62: 364‐369, 2007.
 285.Nozu K, Inagaki T, Fu XJ, Nozu Y, Kaito H, Kanda K, Sekine T, Igarashi T, Nakanishi K, Yoshikawa N, Iijima K, Matsuo M. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. J Med Genet 45: 182‐186, 2008.
 286.Oh U, Jung J. Cellular functions of TMEM16/anoctamin. Pflugers Arch 468: 443‐453, 2016.
 287.Ohta A, Yang SS, Rai T, Chiga M, Sasaki S, Uchida S. Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin‐4 in MDCKII cells. Biochem Biophys Res Commun 349: 804‐808, 2006.
 288.Okusa MD, Unwin RJ, Velazquez H, Giebisch G, Wright FS. Active potassium absorption by the renal distal tubule. Am J Physiol 262: F488‐F493, 1992.
 289.Ousingsawat J, Martins JR, Schreiber R, Rock JR, Harfe BD, Kunzelmann K. Loss of TMEM16A causes a defect in epithelial Ca2+‐dependent chloride transport. J Biol Chem 284: 28698‐28703, 2009.
 290.Palmer BF. Regulation of Potassium Homeostasis. Clin J Am Soc Nephrol 10: 1050‐1060, 2015.
 291.Palmer LG, Frindt G. Amiloride‐sensitive Na channels from the apical membrane of the rat cortical collecting tubule. Proc Natl Acad Sci U S A 83: 2767‐2770, 1986.
 292.Palmer LG, Frindt G. Cl− channels of the distal nephron. Am J Physiol Renal Physiol 291: F1157‐F1168, 2006.
 293.Palmer LG, Sackin H. Electrophysiological analysis of transepithelial transport. In: Seldin DW, Giebisch G, editors. The Kidney: Physiology and Pathophysiology. New York: Raven Press, 1992, pp. 361‐405.
 294.Pannabecker TL. Structure and function of the thin limbs of the loop of Henle. Compr Physiol 2: 2063‐2086, 2012.
 295.Park E, Campbell EB, MacKinnon R. Structure of a CLC chloride ion channel by cryo‐electron microscopy. Nature 541: 500‐505, 2017.
 296.Park E, MacKinnon R. Structure of the CLC‐1 chloride channel from Homo sapiens. Elife 7: pii: e36629, 2018.
 297.Parker MD, Boron WF. The divergence, actions, roles, and relatives of sodium‐coupled bicarbonate transporters. Physiol Rev 93: 803‐959, 2013.
 298.Paulais M, Lourdel S, Teulon J. Properties of an inwardly rectifying K(+) channel in the basolateral membrane of mouse TAL. Am J Physiol Renal Physiol 282: F866‐F876, 2002.
 299.Paulais M, Teulon J. cAMP‐activated chloride channel in the basolateral membrane of the thick ascending limb of the mouse kidney. J Membr Biol 113: 253‐260, 1990.
 300.Paulino C, Kalienkova V, Lam AKM, Neldner Y, Dutzler R. Activation mechanism of the calcium‐activated chloride channel TMEM16A revealed by cryo‐EM. Nature 552: 421‐425, 2017.
 301.Paulino C, Neldner Y, Lam AK, Kalienkova V, Brunner JD, Schenck S, Dutzler R. Structural basis for anion conduction in the calcium‐activated chloride channel TMEM16A. Elife 6: pii: e26232, 2017.
 302.Pech V, Kim YH, Weinstein AM, Everett LA, Pham TD, Wall SM. Angiotensin II increases chloride absorption in the cortical collecting duct in mice through a pendrin‐dependent mechanism. Am J Physiol Renal Physiol 292: F914‐F920, 2007.
 303.Pedemonte N, Galietta LJ. Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94: 419‐459, 2014.
 304.Pena‐Munzenmayer G, Catalan M, Cornejo I, Figueroa CD, Melvin JE, Niemeyer MI, Cid LP, Sepulveda FV. Basolateral localization of native ClC‐2 chloride channels in absorptive intestinal epithelial cells and basolateral sorting encoded by a CBS‐2 domain di‐leucine motif. J Cell Sci 118: 4243‐4252, 2005.
 305.Pena‐Munzenmayer G, George AT, Shull GE, Melvin JE, Catalan MA. Ae4 (Slc4a9) is an electroneutral monovalent cation‐dependent Cl−/HCO3− exchanger. J Gen Physiol 147: 423‐436, 2016.
 306.Penton D, Czogalla J, Wengi A, Himmerkus N, Loffing‐Cueni D, Carrel M, Rajaram RD, Staub O, Bleich M, Schweda F, Loffing J. Extracellular K(+) rapidly controls NaCl cotransporter phosphorylation in the native distal convoluted tubule by Cl(−) ‐dependent and independent mechanisms. J Physiol 594: 6319‐6331, 2016.
 307.Persu A, Devuyst O, Lannoy N, Materne R, Brosnahan G, Gabow PA, Pirson Y, Verellen‐Dumoulin C. CF gene and cystic fibrosis transmembrane conductance regulator expression in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 11: 2285‐2296, 2000.
 308.Petersen OH. Electrophysiology of mammalian gland cells. Physiol Rev 56: 535‐577, 1976.
 309.Petersen OH, Gallacher DV. Electrophysiology of pancreatic and salivary acinar cells. Annu Rev Physiol 50: 65‐80, 1988.
 310.Peti‐Peterdi J, Bebok Z, Lapointe JY, Bell PD. Novel regulation of cell [Na(+)] in macula densa cells: Apical Na(+) recycling by H‐K‐ATPase. Am J Physiol Renal Physiol 282: F324‐F329, 2002.
 311.Peti‐Peterdi J, Harris RC. Macula densa sensing and signaling mechanisms of renin release. J Am Soc Nephrol 21: 1093‐1096, 2010.
 312.Petrovic S, Barone S, Xu J, Conforti L, Ma L, Kujala M, Kere J, Soleimani M. SLC26A7: a basolateral Cl−/HCO3− exchanger specific to intercalated cells of the outer medullary collecting duct. Am J Physiol Renal Physiol 286: F161‐F169, 2004.
 313.Piala AT, Moon TM, Akella R, He H, Cobb MH, Goldsmith EJ. Chloride sensing by WNK1 involves inhibition of autophosphorylation. Sci Signal 7: ra41, 2014.
 314.Picollo A, Liantonio A, Babini E, Camerino DC, Pusch M. Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC‐K chloride channels. J Membr Biol 216: 73‐82, 2007.
 315.Picollo A, Liantonio A, Didonna MP, Elia L, Camerino DC, Pusch M. Molecular determinants of differential pore blocking of kidney CLC‐K chloride channels. EMBO Rep 5: 584‐589, 2004.
 316.Picollo A, Malvezzi M, Accardi A. TMEM16 proteins: Unknown structure and confusing functions. J Mol Biol 427: 94‐105, 2015.
 317.Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC‐4 and ClC‐5. Nature 436: 420‐423, 2005.
 318.Piepenhagen PA, Peters LL, Lux SE, Nelson WJ. Differential expression of Na(+)‐K(+)‐ATPase, ankyrin, fodrin, and E‐cadherin along the kidney nephron. Am J Physiol 269: C1417‐C1432, 1995.
 319.Pinelli L, Nissant A, Edwards A, Lourdel S, Teulon J, Paulais M. Dual regulation of the native ClC‐K2 chloride channel in the distal nephron by voltage and pH. J Gen Physiol 148: 213‐226, 2016.
 320.Planelles G. Chloride transport in the renal proximal tubule. Pflugers Arch 448: 561‐570, 2004.
 321.Planells‐Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, Kucukosmanoglu A, Xu G, Voss FK, Reincke SM, Stauber T, Blomen VA, Vis DJ, Wessels LF, Brummelkamp TR, Borst P, Rottenberg S, Jentsch TJ. Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt‐based anti‐cancer drugs. EMBO J 34: 2993‐3008, 2015.
 322.Pusch M, Jordt SE, Stein V, Jentsch TJ. Chloride dependence of hyperpolarization‐activated chloride channel gates. J Physiol 515(Pt 2): 341‐353, 1999.
 323.Pusch M, Liantonio A, Bertorello L, Accardi A, De Luca A, Pierno S, Tortorella V, Camerino DC. Pharmacological characterization of chloride channels belonging to the ClC family by the use of chiral clofibric acid derivatives. Mol Pharmacol 58: 498‐507, 2000.
 324.Pusch M, Ludewig U, Rehfeldt A, Jentsch TJ. Gating of the voltage‐dependent chloride channel CIC‐0 by the permeant anion. Nature 373: 527‐531, 1995.
 325.Pusch M, Steinmeyer K, Koch MC, Jentsch TJ. Mutations in dominant human myotonia congenita drastically alter the voltage dependence of the CIC‐1 chloride channel. Neuron 15: 1455‐1463, 1995.
 326.Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A. SWELL1, a plasma membrane protein, is an essential component of volume‐regulated anion channel. Cell 157: 447‐458, 2014.
 327.Qu Z, Wei RW, Hartzell HC. Characterization of Ca2+‐activated Cl− currents in mouse kidney inner medullary collecting duct cells. Am J Physiol Renal Physiol 285: F326‐F335, 2003.
 328.Quentin F, Chambrey R, Trinh‐Trang‐Tan MM, Fysekidis M, Cambillau M, Paillard M, Aronson PS, Eladari D. The Cl−/HCO3− exchanger pendrin in the rat kidney is regulated in response to chronic alterations in chloride balance. Am J Physiol Renal Physiol 287: F1179‐F1188, 2004.
 329.Reeves WB, Winters CJ, Andreoli TE. Chloride channels in the loop of Henle. Annu Rev Physiol 63: 631‐645, 2001.
 330.Reeves WB, Winters CJ, Filipovic DM, Andreoli TE. Cl− channels in basolateral renal medullary vesicles. IX. Channels from mouse MTAL cell patches and medullary vesicles. Am J Physiol 269: F621‐F627, 1995.
 331.Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben‐Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R. KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function. Proc Natl Acad Sci U S A 107: 14490‐14495, 2010.
 332.Ren Y, Yu H, Wang H, Carretero OA, Garvin JL. Nystatin and valinomycin induce tubuloglomerular feedback. Am J Physiol Renal Physiol 281: F1102‐F1108, 2001.
 333.Riazuddin S, Anwar S, Fischer M, Ahmed ZM, Khan SY, Janssen AG, Zafar AU, Scholl U, Husnain T, Belyantseva IA, Friedman PL, Friedman TB, Fahlke C. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am J Hum Genet 85: 273‐280, 2009.
 334.Rickheit G, Maier H, Strenzke N, Andreescu CE, De Zeeuw CI, Muenscher A, Zdebik AA, Jentsch TJ. Endocochlear potential depends on Cl− channels: Mechanism underlying deafness in Bartter syndrome IV. EMBO J 27: 2907‐2917, 2008.
 335.Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245: 1066‐1073, 1989.
 336.Robson L, Hunter M. Regulation of an outwardly rectifying Cl− conductance in single proximal tubule cells isolated from frog kidney. J Physiol 498(Pt 2): 409‐417, 1997.
 337.Robson L, Hunter M. Role of cell volume and protein kinase C in regulation of a Cl‐ conductance in single proximal tubule cells of Rana temporaria. J Physiol 480(Pt 1): 1‐7, 1994.
 338.Robson L, Hunter M. Volume regulatory responses in frog isolated proximal cells. Pflugers Arch 428: 60‐68, 1994.
 339.Romanenko VG, Nakamoto T, Catalan MA, Gonzalez‐Begne M, Schwartz GJ, Jaramillo Y, Sepulveda FV, Figueroa CD, Melvin JE. Clcn2 encodes the hyperpolarization‐activated chloride channel in the ducts of mouse salivary glands. Am J Physiol Gastrointest Liver Physiol 295: G1058‐G1067, 2008.
 340.Roy A, Al‐bataineh MM, Pastor‐Soler NM. Collecting duct intercalated cell function and regulation. Clin J Am Soc Nephrol 10: 305‐324, 2015.
 341.Royaux IE, Wall SM, Karniski LP, Everett LA, Suzuki K, Knepper MA, Green ED. Pendrin, encoded by the Pendred syndrome gene, resides in the apical region of renal intercalated cells and mediates bicarbonate secretion. Proc Natl Acad Sci U S A 98: 4221‐4226, 2001.
 342.Rubera I, Tauc M, Bidet M, Poujeol C, Cuiller B, Watrin A, Touret N, Poujeol P. Chloride currents in primary cultures of rabbit proximal and distal convoluted tubules. Am J Physiol 275: F651‐F663, 1998.
 343.Rubera I, Tauc M, Poujeol C, Bohn MT, Bidet M, De Renzis G, Poujeol P. Cl− and K+ conductances activated by cell swelling in primary cultures of rabbit distal bright convoluted tubules. Am J Physiol 273: F680‐697, 1997.
 344.Rychkov GY, Pusch M, Astill DS, Roberts ML, Jentsch TJ, Bretag AH. Concentration and pH dependence of skeletal muscle chloride channel ClC‐1. J Physiol 497(Pt 2): 423‐435, 1996.
 345.Salomonsson M, Gonzalez E, Kornfeld M, Persson AE. The cytosolic chloride concentration in macula densa and cortical thick ascending limb cells. Acta Physiol Scand 147: 305‐313, 1993.
 346.Sanchez‐Rodriguez JE, De Santiago‐Castillo JA, Contreras‐Vite JA, Nieto‐Delgado PG, Castro‐Chong A, Arreola J. Sequential interaction of chloride and proton ions with the fast gate steer the voltage‐dependent gating in ClC‐2 chloride channels. J Physiol 590: 4239‐4253, 2012.
 347.Sansom SC, La BQ, Carosi SL. Double‐barreled chloride channels of collecting duct basolateral membrane. Am J Physiol 259: F46‐52, 1990.
 348.Sansom SC, Weinman EJ, O'Neil RG. Microelectrode assessment of chloride‐conductive properties of cortical collecting duct. Am J Physiol 247: F291‐F302, 1984.
 349.Sauve R, Cai S, Garneau L, Klein H, Parent L. pH and external Ca(2+) regulation of a small conductance Cl(−) channel in kidney distal tubule. Biochim Biophys Acta 1509: 73‐85, 2000.
 350.Saviane C, Conti F, Pusch M. The muscle chloride channel ClC‐1 has a double‐barreled appearance that is differentially affected in dominant and recessive myotonia. J Gen Physiol 113: 457‐468, 1999.
 351.Schafer JA, Patlak CS, Andreoli TE. A component of fluid absorption linked to passive ion flows in the superficial pars recta. J Gen Physiol 66: 445‐471, 1975.
 352.Scheel O, Zdebik AA, Lourdel S, Jentsch TJ. Voltage‐dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436: 424‐427, 2005.
 353.Schild L, Aronson PS, Giebisch G. Basolateral transport pathways for K+ and Cl− in rabbit proximal tubule: Effects on cell volume. Am J Physiol 260: F101‐F109, 1991.
 354.Schlatter E, Frobe U, Greger R. Ion conductances of isolated cortical collecting duct cells. Pflugers Arch 421: 381‐387, 1992.
 355.Schlatter E, Greger R, Schafer JA. Principal cells of cortical collecting ducts of the rat are not a route of transepithelial Cl− transport. Pflugers Arch 417: 317‐323, 1990.
 356.Schlatter E, Salomonsson M, Persson AE, Greger R. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl‐K+ cotransport. Pflugers Arch 414: 286‐290, 1989.
 357.Schlatter E, Schafer JA. Electrophysiological studies in principal cells of rat cortical collecting tubules. ADH increases the apical membrane Na+‐conductance. Pflugers Arch 409: 81‐92, 1987.
 358.Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, Waldegger S. Salt wasting and deafness resulting from mutations in two chloride channels. N Engl J Med 350: 1314‐1319, 2004.
 359.Schmitt BM, Biemesderfer D, Romero MF, Boulpaep EL, Boron WF. Immunolocalization of the electrogenic Na+‐HCO‐3 cotransporter in mammalian and amphibian kidney. Am J Physiol 276: F27‐F38, 1999.
 360.Schnermann J. Homer W. Smith Award lecture. The juxtaglomerular apparatus: From anatomical peculiarity to physiological relevance. J Am Soc Nephrol 14: 1681‐1694, 2003.
 361.Schnermann J, Briggs JP. Tubuloglomerular feedback: Mechanistic insights from gene‐manipulated mice. Kidney Int 74: 418‐426, 2008.
 362.Schober AL, Wilson CS, Mongin AA. Molecular composition and heterogeneity of the LRRC8‐containing swelling‐activated osmolyte channels in primary rat astrocytes. J Physiol 595: 6939‐6951, 2017.
 363.Scholl U, Hebeisen S, Janssen AG, Muller‐Newen G, Alekov A, Fahlke C. Barttin modulates trafficking and function of ClC‐K channels. Proc Natl Acad Sci U S A 103: 11411‐11416, 2006.
 364.Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson‐Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP. CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet 50: 349‐354, 2018.
 365.Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium‐activated chloride channel subunit. Cell 134: 1019‐1029, 2008.
 366.Schuster VL. Function and regulation of collecting duct intercalated cells. Annu Rev Physiol 55: 267‐288, 1993.
 367.Schweda F. Salt feedback on the renin‐angiotensin‐aldosterone system. Pflugers Arch 467: 565‐576, 2015.
 368.Segal AS, Geibel J, Boulpaep EL. A chloride channel resembling CFTR on the basolateral membrane of rabbit proximal tubule. J Am Soc Nephrol 4: 879a, 1993.
 369.Seki G, Taniguchi S, Uwatoko S, Suzuki K, Kurokawa K. Activation of the basolateral Cl− conductance by cAMP in rabbit renal proximal tubule S3 segments. Pflugers Arch 430: 88‐95, 1995.
 370.Seki G, Taniguchi S, Uwatoko S, Suzuki K, Kurokawa K. Evidence for conductive Cl− pathway in the basolateral membrane of rabbit renal proximal tubule S3 segment. J Clin Invest 92: 1229‐1235, 1993.
 371.Sepulveda FV, Pablo Cid L, Teulon J, Niemeyer MI. Molecular aspects of structure, gating, and physiology of pH‐sensitive background K2P and Kir K+‐transport channels. Physiol Rev 95: 179‐217, 2015.
 372.Seyberth HW, Schlingmann KP. Bartter‐ and Gitelman‐like syndromes: Salt‐losing tubulopathies with loop or DCT defects. Pediatr Nephrol 26: 1789‐1802, 2011.
 373.Seys E, Andrini O, Keck M, Mansour‐Hendili L, Courand PY, Simian C, Deschenes G, Kwon T, Bertholet‐Thomas A, Bobrie G, Borde JS, Bourdat‐Michel G, Decramer S, Cailliez M, Krug P, Cozette P, Delbet JD, Dubourg L, Chaveau D, Fila M, Jourde‐Chiche N, Knebelmann B, Lavocat MP, Lemoine S, Djeddi D, Llanas B, Louillet F, Merieau E, Mileva M, Mota‐Vieira L, Mousson C, Nobili F, Novo R, Roussey‐Kesler G, Vrillon I, Walsh SB, Teulon J, Blanchard A, Vargas‐Poussou R. Clinical and genetic spectrum of Bartter syndrome type 3. J Am Soc Nephrol 28: 2540‐2552, 2017.
 374.Shafique S, Siddiqi S, Schraders M, Oostrik J, Ayub H, Bilal A, Ajmal M, Seco CZ, Strom TM, Mansoor A, Mazhar K, Shah ST, Hussain A, Azam M, Kremer H, Qamar R. Genetic spectrum of autosomal recessive non‐syndromic hearing loss in Pakistani families. PLoS One 9: e100146, 2014.
 375.Shekarabi M, Zhang J, Khanna AR, Ellison DH, Delpire E, Kahle KT. WNK kinase signaling in ion homeostasis and human disease. Cell Metab 25: 285‐299, 2017.
 376.Shintani Y, Marunaka Y. Regulation of single Cl− channel conductance by insulin and tyrosine phosphatase. Biochem Biophys Res Commun 218: 142‐147, 1996.
 377.Simon DB, Bindra RS, Mansfield TA, Nelson‐Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez‐Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet 17: 171‐178, 1997.
 378.Simon DB, Karet FE, Rodriguez‐Soriano J, Hamdan JH, DiPietro A, Trachtman H, Sanjad SA, Lifton RP. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet 14: 152‐156, 1996.
 379.Simon DB, Lifton RP. The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes. Am J Physiol 271: F961‐966, 1996.
 380.Simon DB, Lifton RP. Mutations in renal ion transporters cause Gitelman's and Bartter's syndromes of inherited hypokalemic alkalosis. Adv Nephrol Necker Hosp 27: 343‐359, 1997.
 381.Simon DB, Nelson‐Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide‐sensitive Na‐Cl cotransporter. Nat Genet 12: 24‐30, 1996.
 382.Sinkkonen ST, Mansikkamaki S, Moykkynen T, Luddens H, Uusi‐Oukari M, Korpi ER. Receptor subtype‐dependent positive and negative modulation of GABA(A) receptor function by niflumic acid, a nonsteroidal anti‐inflammatory drug. Mol Pharmacol 64: 753‐763, 2003.
 383.Soleimani M, Greeley T, Petrovic S, Wang Z, Amlal H, Kopp P, Burnham CE. Pendrin: An apical Cl−/OH−/HCO3− exchanger in the kidney cortex. Am J Physiol Renal Physiol 280: F356‐F364, 2001.
 384.Souza‐Menezes J, Morales MM. CFTR structure and function: Is there a role in the kidney? Biophys Rev 1: 3‐12, 2009.
 385.Staley K, Smith R, Schaack J, Wilcox C, Jentsch TJ. Alteration of GABAA receptor function following gene transfer of the CLC‐2 chloride channel. Neuron 17: 543‐551, 1996.
 386.Stanton BA. Characterization of apical and basolateral membrane conductances of rat inner medullary collecting duct. Am J Physiol 256: F862‐F868, 1989.
 387.Staruschenko A. Regulation of transport in the connecting tubule and cortical collecting duct. Compr Physiol 2: 1541‐1584, 2012.
 388.Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D. Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination. EMBO J 16: 6325‐6336, 1997.
 389.Stauber T, Weinert S, Jentsch TJ. Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2: 1701‐1744, 2012.
 390.Stehberger PA, Shmukler BE, Stuart‐Tilley AK, Peters LL, Alper SL, Wagner CA. Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl−/HCO3− exchanger (slc4a1). J Am Soc Nephrol 18: 1408‐1418, 2007.
 391.Steinke KV, Gorinski N, Wojciechowski D, Todorov V, Guseva D, Ponimaskin E, Fahlke C, Fischer M. Human CLC‐K channels require palmitoylation of their accessory subunit barttin to be functional. J Biol Chem 290: 17390‐17400, 2015.
 392.Steinmeyer K, Klocke R, Ortland C, Gronemeier M, Jockusch H, Grunder S, Jentsch TJ. Inactivation of muscle chloride channel by transposon insertion in myotonic mice. Nature 354: 304‐308, 1991.
 393.Steinmeyer K, Ortland C, Jentsch TJ. Primary structure and functional expression of a developmentally regulated skeletal muscle chloride channel. Nature 354: 301‐304, 1991.
 394.Stockand JD, Vallon V, Ortiz P. In vivo and ex vivo analysis of tubule function. Compr Physiol 2: 2495‐2525, 2012.
 395.Stolting G, Fischer M, Fahlke C. CLC channel function and dysfunction in health and disease. Front Physiol 5: 378, 2014.
 396.Su XT, Wang WH. The expression, regulation, and function of Kir4.1 (Kcnj10) in the mammalian kidney. Am J Physiol Renal Physiol 311: F12‐F15, 2016.
 397.Sullivan LP, Wallace DP, Grantham JJ. Epithelial transport in polycystic kidney disease. Physiol Rev 78: 1165‐1191, 1998.
 398.Suzuki J, Umeda M, Sims PJ, Nagata S. Calcium‐dependent phospholipid scrambling by TMEM16F. Nature 468: 834‐838, 2010.
 399.Syeda R, Qiu Z, Dubin AE, Murthy SE, Florendo MN, Mason DE, Mathur J, Cahalan SM, Peters EC, Montal M, Patapoutian A. LRRC8 proteins form volume‐regulated anion channels that sense ionic strength. Cell 164: 499‐511, 2016.
 400.Tajima T, Nawate M, Takahashi Y, Mizoguchi Y, Sugihara S, Yoshimoto M, Murakami M, Adachi M, Tachibana K, Mochizuki H, Fujieda K. Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome. Endocr J 53: 647‐652, 2006.
 401.Takahashi D, Mori T, Nomura N, Khan MZ, Araki Y, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S. WNK4 is the major WNK positively regulating NCC in the mouse kidney. Biosci Rep 34: pii: e00107, 2014.
 402.Takahashi N, Kondo Y, Ito O, Igarashi Y, Omata K, Abe K. Vasopressin stimulates Cl− transport in ascending thin limb of Henle's loop in hamster. J Clin Invest 95: 1623‐1627, 1995.
 403.Takiar V, Nishio S, Seo‐Mayer P, King JD, Jr., Li H, Zhang L, Karihaloo A, Hallows KR, Somlo S, Caplan MJ. Activating AMP‐activated protein kinase (AMPK) slows renal cystogenesis. Proc Natl Acad Sci U S A 108: 2462‐2467, 2011.
 404.Tan H, Bungert‐Plumke S, Fahlke C, Stolting G. Reduced membrane insertion of CLC‐K by V33L barttin results in loss of hearing, but leaves kidney function intact. Front Physiol 8: 269, 2017.
 405.Terada Y, Knepper MA. Thiazide‐sensitive NaCl absorption in rat cortical collecting duct. Am J Physiol 259: F519‐F528, 1990.
 406.Terker AS, Ellison DH. Renal mineralocorticoid receptor and electrolyte homeostasis. Am J Physiol Regul Integr Comp Physiol 309: R1068‐R1070, 2015.
 407.Terker AS, Zhang C, Erspamer KJ, Gamba G, Yang CL, Ellison DH. Unique chloride‐sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int 89: 127‐134, 2016.
 408.Terker AS, Zhang C, McCormick JA, Lazelle RA, Zhang C, Meermeier NP, Siler DA, Park HJ, Fu Y, Cohen DM, Weinstein AM, Wang WH, Yang CL, Ellison DH. Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride. Cell Metab 21: 39‐50, 2015.
 409.Thiemann A, Grunder S, Pusch M, Jentsch TJ. A chloride channel widely expressed in epithelial and non‐epithelial cells. Nature 356: 57‐60, 1992.
 410.Tomita K, Pisano JJ, Burg MB, Knepper MA. Effects of vasopressin and bradykinin on anion transport by the rat cortical collecting duct. Evidence for an electroneutral sodium chloride transport pathway. J Clin Invest 77: 136‐141, 1986.
 411.Tomita K, Pisano JJ, Knepper MA. Control of sodium and potassium transport in the cortical collecting duct of the rat. Effects of bradykinin, vasopressin, and deoxycorticosterone. J Clin Invest 76: 132‐136, 1985.
 412.Uchida S, Sasaki S. Function of chloride channels in the kidney. Annu Rev Physiol 67: 759‐778, 2005.
 413.Uchida S, Sasaki S, Furukawa T, Hiraoka M, Imai T, Hirata Y, Marumo F. Molecular cloning of a chloride channel that is regulated by dehydration and expressed predominantly in kidney medulla. J Biol Chem 268: 3821‐3824, 1993.
 414.Uchida S, Sasaki S, Nitta K, Uchida K, Horita S, Nihei H, Marumo F. Localization and functional characterization of rat kidney‐specific chloride channel, ClC‐K1. J Clin Invest 95: 104‐113, 1995.
 415.Ulmasov B, Bruno J, Oshima K, Cheng YW, Holly SP, Parise LV, Egan TM, Edwards JC. CLIC1 null mice demonstrate a role for CLIC1 in macrophage superoxide production and tissue injury. Physiol Rep 5: pii: e13169, 2017.
 416.Vallon V, Schroth J, Lang F, Kuhl D, Uchida S. Expression and phosphorylation of the Na+‐Cl− cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. Am J Physiol Renal Physiol 297: F704‐F712, 2009.
 417.Vandewalle A, Cluzeaud F, Bens M, Kieferle S, Steinmeyer K, Jentsch TJ. Localization and induction by dehydration of ClC‐K chloride channels in the rat kidney. Am J Physiol 272: F678‐F688, 1997.
 418.Vandorpe D, Kizer N, Ciampollilo F, Moyer B, Karlson K, Guggino WB, Stanton BA. CFTR mediates electrogenic chloride secretion in mouse inner medullary collecting duct (mIMCD‐K2) cells. Am J Physiol 269: C683‐C689, 1995.
 419.Vargas‐Poussou R, Dahan K, Kahila D, Venisse A, Riveira‐Munoz E, Debaix H, Grisart B, Bridoux F, Unwin R, Moulin B, Haymann JP, Vantyghem MC, Rigothier C, Dussol B, Godin M, Nivet H, Dubourg L, Tack I, Gimenez‐Roqueplo AP, Houillier P, Blanchard A, Devuyst O, Jeunemaitre X. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol 22: 693‐703, 2011.
 420.Vargas‐Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, Planelles G, Dechaux M, Miller RT, Antignac C. Functional characterization of a calcium‐sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter‐like syndrome. J Am Soc Nephrol 13: 2259‐2266, 2002.
 421.Vazquez N, Monroy A, Dorantes E, Munoz‐Clares RA, Gamba G. Functional differences between flounder and rat thiazide‐sensitive Na‐Cl cotransporter. Am J Physiol Renal Physiol 282: F599‐F607, 2002.
 422.Velazquez H, Good DW, Wright FS. Mutual dependence of sodium and chloride absorption by renal distal tubule. Am J Physiol 247: F904‐911, 1984.
 423.Velazquez H, Silva T. Cloning and localization of KCC4 in rabbit kidney: Expression in distal convoluted tubule. Am J Physiol Renal Physiol 285: F49‐58, 2003.
 424.Verlander JW, Hassell KA, Royaux IE, Glapion DM, Wang ME, Everett LA, Green ED, Wall SM. Deoxycorticosterone upregulates PDS (Slc26a4) in mouse kidney: Role of pendrin in mineralocorticoid‐induced hypertension. Hypertension 42: 356‐362, 2003.
 425.Voets T, Droogmans G, Raskin G, Eggermont J, Nilius B. Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume‐regulated anion channels. Proc Natl Acad Sci U S A 96: 5298‐5303, 1999.
 426.Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N, Andrade‐Navarro MA, von Kries JP, Stauber T, Jentsch TJ. Identification of LRRC8 heteromers as an essential component of the volume‐regulated anion channel VRAC. Science 344: 634‐638, 2014.
 427.Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Matsuo H, Murata T, Nomura S, Asano T, Kawaguchi H, Nonoyama S, Rai T, Sasaki S, Uchida S. Impaired KLHL3‐mediated ubiquitination of WNK4 causes human hypertension. Cell Rep 3: 858‐868, 2013.
 428.Waldegger S, Jeck N, Barth P, Peters M, Vitzthum H, Wolf K, Kurtz A, Konrad M, Seyberth HW. Barttin increases surface expression and changes current properties of ClC‐K channels. Pflugers Arch 444: 411‐418, 2002.
 429.Waldegger S, Jentsch TJ. Functional and structural analysis of ClC‐K chloride channels involved in renal disease. J Biol Chem 275: 24527‐24533, 2000.
 430.Wall SM, Kim YH, Stanley L, Glapion DM, Everett LA, Green ED, Verlander JW. NaCl restriction upregulates renal Slc26a4 through subcellular redistribution: Role in Cl− conservation. Hypertension 44: 982‐987, 2004.
 431.Wall SM, Lazo‐Fernandez Y. The role of pendrin in renal physiology. Annu Rev Physiol 77: 363‐378, 2015.
 432.Wallace DP. Cyclic AMP‐mediated cyst expansion. Biochim Biophys Acta 1812: 1291‐1300, 2011.
 433.Wang C, Chen Y, Zheng B, Zhu M, Fan J, Wang J, Jia Z, Huang S, Zhang A. Novel compound heterozygous CLCNKB gene mutations (c.1755A>G/c.848_850delTCT) cause classic Bartter syndrome. Am J Physiol Renal Physiol 315: F844‐F851, 2018.
 434.Wang MX, Cuevas CA, Su XT, Wu P, Gao ZX, Lin DH, McCormick JA, Yang CL, Wang WH, Ellison DH. Potassium intake modulates the thiazide‐sensitive sodium‐chloride cotransporter (NCC) activity via the Kir4.1 potassium channel. Kidney Int 93: 893‐902, 2018.
 435.Wang T, Agulian SK, Giebisch G, Aronson PS. Effects of formate and oxalate on chloride absorption in rat distal tubule. Am J Physiol 264: F730‐F736, 1993.
 436.Wang T, Malnic G, Giebisch G, Chan YL. Renal bicarbonate reabsorption in the rat. IV. Bicarbonate transport mechanisms in the early and late distal tubule. J Clin Invest 91: 2776‐2784, 1993.
 437.Wang WH. Basolateral Kir4.1 activity in the distal convoluted tubule regulates K secretion by determining NaCl cotransporter activity. Curr Opin Nephrol Hypertens 25: 429‐435, 2016.
 438.Wang Y, Soyombo AA, Shcheynikov N, Zeng W, Dorwart M, Marino CR, Thomas PJ, Muallem S. Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3− secretion: Relevance to cystic fibrosis. EMBO J 25: 5049‐5057, 2006.
 439.Wangemann P, Wittner M, Di Stefano A, Englert HC, Lang HJ, Schlatter E, Greger R. Cl(−)‐channel blockers in the thick ascending limb of the loop of Henle. Structure activity relationship. Pflugers Arch 407(Suppl 2): S128‐S141, 1986.
 440.Weinreich F, Jentsch TJ. Pores formed by single subunits in mixed dimers of different CLC chloride channels. J Biol Chem 276: 2347‐2353, 2001.
 441.Weinstein AM. A mathematical model of rat distal convoluted tubule. I. Cotransporter function in early DCT. Am J Physiol Renal Physiol 289: F699‐F720, 2005.
 442.Weinstein AM. A mathematical model of the outer medullary collecting duct of the rat. Am J Physiol Renal Physiol 279: F24‐45, 2000.
 443.Welling PA. Roles and Regulation of Renal K Channels. Annu Rev Physiol 78: 415‐435, 2016.
 444.Welling PA, Ho K. A comprehensive guide to the ROMK potassium channel: Form and function in health and disease. Am J Physiol Renal Physiol 297: F849‐F863, 2009.
 445.Welling PA, O'Neil RG. Cell swelling activates basolateral membrane Cl and K conductances in rabbit proximal tubule. Am J Physiol 258: F951‐F962, 1990.
 446.Welling PA, O'Neil RG. Ionic conductive properties of rabbit proximal straight tubule basolateral membrane. Am J Physiol 258: F940‐F950, 1990.
 447.Westland R, Hack WW, van der Horst HJ, Uittenbogaard LB, van Hagen JM, van der Valk P, Kamsteeg EJ, van den Heuvel LP, van Wijk JA. Bartter syndrome type III and congenital anomalies of the kidney and urinary tract: An antenatal presentation. Clin Nephrol 78: 492‐496, 2012.
 448.Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, Hebert SC, Gamba G, Lifton RP. Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na‐Cl cotransporter is inhibited by wild‐type but not mutant WNK4. Proc Natl Acad Sci U S A 100: 680‐684, 2003.
 449.Winters CJ, Reeves WB, Andreoli TE. Cl− channels in basolateral renal medullary membranes: III. Determinants of single‐channel activity. J Membr Biol 118: 269‐278, 1990.
 450.Wojciechowski D, Fischer M, Fahlke C. Tryptophan scanning mutagenesis identifies the molecular determinants of distinct barttin functions. J Biol Chem 290: 18732‐18743, 2015.
 451.Wright FS, Schnermann J. Interference with feedback control of glomerular filtration rate by furosemide, triflocin, and cyanide. J Clin Invest 53: 1695‐1708, 1974.
 452.Wu P, Wang M, Luan H, Li L, Wang L, Wang WH, Gu R. Angiotensin II stimulates basolateral 10‐pS Cl channels in the thick ascending limb. Hypertension 61: 1211‐1217, 2013.
 453.Xiao Q, Hartzell HC, Yu K. Bestrophins and retinopathies. Pflugers Arch 460: 559‐569, 2010.
 454.Xu J, Song P, Nakamura S, Miller M, Barone S, Alper SL, Riederer B, Bonhagen J, Arend LJ, Amlal H, Seidler U, Soleimani M. Deletion of the chloride transporter slc26a7 causes distal renal tubular acidosis and impairs gastric acid secretion. J Biol Chem 284: 29470‐29479, 2009.
 455.Xu J, Worrell RT, Li HC, Barone SL, Petrovic S, Amlal H, Soleimani M. Chloride/bicarbonate exchanger SLC26A7 is localized in endosomes in medullary collecting duct cells and is targeted to the basolateral membrane in hypertonicity and potassium depletion. J Am Soc Nephrol 17: 956‐967, 2006.
 456.Yamauchi K, Rai T, Kobayashi K, Sohara E, Suzuki T, Itoh T, Suda S, Hayama A, Sasaki S, Uchida S. Disease‐causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci U S A 101: 4690‐4694, 2004.
 457.Yang B, Sonawane ND, Zhao D, Somlo S, Verkman AS. Small‐molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol 19: 1300‐1310, 2008.
 458.Yang CL, Angell J, Mitchell R, Ellison DH. WNK kinases regulate thiazide‐sensitive Na‐Cl cotransport. J Clin Invest 111: 1039‐1045, 2003.
 459.Yang SS, Morimoto T, Rai T, Chiga M, Sohara E, Ohno M, Uchida K, Lin SH, Moriguchi T, Shibuya H, Kondo Y, Sasaki S, Uchida S. Molecular pathogenesis of pseudohypoaldosteronism type II: Generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell Metab 5: 331‐344, 2007.
 460.Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A confers receptor‐activated calcium‐dependent chloride conductance. Nature 455: 1210‐1215, 2008.
 461.Yoshitomi K, Kondo Y, Imai M. Evidence for conductive Cl− pathways across the cell membranes of the thin ascending limb of Henle's loop. J Clin Invest 82: 866‐871, 1988.
 462.Yoshitomi K, Shimizu T, Taniguchi J, Imai M. Electrophysiological characterization of rabbit distal convoluted tubule cell. Pflugers Arch 414: 457‐463, 1989.
 463.Yu AS. Claudins and the kidney. J Am Soc Nephrol 26: 11‐19, 2015.
 464.Yu Y, Xu C, Pan X, Ren H, Wang W, Meng X, Huang F, Chen N. Identification and functional analysis of novel mutations of the CLCNKB gene in Chinese patients with classic Bartter syndrome. Clin Genet 77: 155‐162, 2010.
 465.Zaika O, Mamenko M, Boukelmoune N, Pochynyuk O. IGF‐1 and insulin exert opposite actions on ClC‐K2 activity in the cortical collecting ducts. Am J Physiol Renal Physiol 308: F39‐F48, 2015.
 466.Zaika O, Tomilin V, Mamenko M, Bhalla V, Pochynyuk O. New perspective of ClC‐Kb/2 Cl− channel physiology in the distal renal tubule. Am J Physiol Renal Physiol 310: F923‐F930, 2016.
 467.Zdebik AA, Cuffe JE, Bertog M, Korbmacher C, Jentsch TJ. Additional disruption of the ClC‐2 Cl(−) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models. J Biol Chem 279: 22276‐22283, 2004.
 468.Zelikovic I, Szargel R, Hawash A, Labay V, Hatib I, Cohen N, Nakhoul F. A novel mutation in the chloride channel gene, CLCNKB, as a cause of Gitelman and Bartter syndromes. Kidney Int 63: 24‐32, 2003.
 469.Zhang C, Wang L, Zhang J, Su XT, Lin DH, Scholl UI, Giebisch G, Lifton RP, Wang WH. KCNJ10 determines the expression of the apical Na‐Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1). Proc Natl Acad Sci U S A 111: 11864‐11869, 2014.
 470.Zhuo JL, Li XC. Proximal nephron. Compr Physiol 3: 1079‐1123, 2013.
 471.Zifarelli G, Liantonio A, Gradogna A, Picollo A, Gramegna G, De Bellis M, Murgia AR, Babini E, Camerino DC, Pusch M. Identification of sites responsible for the potentiating effect of niflumic acid on ClC‐Ka kidney chloride channels. Br J Pharmacol 160: 1652‐1661, 2010.
 472.Zuniga L, Niemeyer MI, Varela D, Catalan M, Cid LP, Sepulveda FV. The voltage‐dependent ClC‐2 chloride channel has a dual gating mechanism. J Physiol 555: 671‐682, 2004.

 

Teaching Material

J. Teulon, G. Planelles, F. V. Sepúlveda, O. Andrini, S. Lourdel, M. Paulais. Renal Chloride Channels in Relation to Sodium Chloride Transport. Compr Physiol 9: 2019, 301-342.

Didactic Synopsis

Major Teaching Points:

  • NaCl absorption involves basolateral chloride channels in most parts of the renal tubule, except the proximal tubule.
  • The predominant chloride channels in the kidneys are ClC-Ka/ClC-K1 and ClC-Kb/ClC-K2 belonging to the ClC family of chloride channels and exchangers.
  • Both channels require the regulatory subunit barttin for proper expression in the membrane and regulation.
  • ClC-Ka/ClC-K1 is expressed mostly in the thin ascending limb and the medullary thick ascending limb. It helps building the corticomedullary concentration gradient.
  • ClC-Kb/ClC-K2 participates to the basolateral step of chloride absorption in the thick ascending limb and the distal nephron.
  • No ClC-K channel is expressed in the proximal tubule, a nephron segment in which chloride absorption occurs mainly via the paracellular pathway.
  • CFTR is present in the proximal tubule, with a role in endocytosis, and in the collecting tubule, with no ascertained function.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends for some of the figures are written to be useful for teaching.,

Figure 1 Ca2+-activated, volume-regulated, and hyperpolarization-activated chloride currents in isolated rat parotid acinar cells. These experiments were done using the whole-cell recording variant of the patch-clamp technique. A fire-polished glass electrode is put into contact with clean plasma membrane of one intact cell. Negative pressure is applied until obtaining a close contact between membrane and glass as monitored with leak resistance measurements (R > 1 gigaOhm). The membrane patch is then ruptured with further negative pressure to establish direct contact between the liquid in the glass pipette and the cell interior. A series of voltage pulses can be applied to the cell interior that give current responses, which are dependent on the population of channels present in the cell tested. As usual in this type of illustration, the current traces obtained at each voltage pulse are overlaid. The composition of the solutions is designed to isolate one type of current. For instance, K+ currents can be avoided by eliminating K+ ions and adding K+ channel inhibitors. In the case of these experiments, it was possible to select one type of chloride current by manipulating intracellular calcium, osmolarity, and voltage stimulation: Ca2+-dependent currents were recorded in 100 nmol/L free calcium concentration under positive osmotic pressure of 26 mosm.kg−1 to inactivate volume-regulated currents. Volume-regulated currents were obtained under negative osmotic pressure of 13 mosm.kg−1 in the presence of EGTA to inactivate Ca2+-dependent currents. Hyperpolarization-activated currents were recorded in the presence of 10 mmol/L EGTA and under positive osmotic pressure.

Figure 2 The selectivity filter (SF) in proteins of the CLC family. ClC channels and transporters are proteins present in the plasma membrane that are large enough to protrude both to the intra- and extracellular side of the membrane. They allow selective passage of ions from one side to the other through a tunnel, named the channel pore, that traverses the thickness of the protein. A constriction in the pore constitutes the SF. This pore segment is generally narrow enough so the ions traverse it in single file. Selectivity is given by the dimensions and the chemical nature of the wall of the SF. The SF in ClC proteins is made of three binding sites in a row. Interactions of permeating ions with the binding sites are weak, H-bonds shown by dashed lines rather than ionic interactions, to ensure that the ions do not remain irreversibly bound but are pushed along by electrical and chemical (concentration gradient) forces. Three ion-binding sites are identified in a bacterial ClC, an anatomy that is repeated in other members of the family. The left hand side shows what is believed to be a closed conformation of the protein. In this conformation Sint and Scen, the inner and central binding sites, are occupied by Cl ions (red circles), while outermost Sext is occupied by a glutamate (E148) side chain that would obstruct free passage of ions. Other amino acid residues and two α-helices that form the binding sites are also shown. An open conformation in which the glutamate side chain is flipped out of Sext into the extracellular vestibule and the site is occupied by a third Cl ion, is shown on the right. This flipping in and out of the SF might at the basis of the way ClC channels open and close in response to a variety of stimuli. Whether this is the case for all ClC proteins is presently an area of active research. From Dutzler et al, Science 300: 108-112, 2003 (91). Reprinted with permission from AAAS.

Figure 3 10-pS chloride channel of the ClC-K2 type is present at high density in the basolateral membrane. These experiments were done using the cell-attached variant of the patch-clamp technique. The patch is formed as explained in the previous teaching point (Figure ) but the membrane patch is not ruptured. Thus, the cell is intact. In this condition, the clamp potential Vc superimposes on the spontaneous membrane potential, hyperpolarizing or depolarizing membrane patch for negative or positive Vc, respectively. To determine the closed level for the currents due to channel activity, it is necessary to inhibit the channels. In the cell-free configuration, this is easily done by applying an inside solution the membrane patch containing an inhibitor. Here, the authors used the property of the channel to be inhibited at acid pH. The Na-free NEM-supplemented solution induced intracellular acidification by inhibiting Na+/H+ exchange and H+ pump. The closed current level allowed calculating time-averaged current and number of open channels (NPo). Note that in the absence of this protocol, the number of channels present in the patch could not have been calculated, especially for this channel, which is present at high density in the basolateral membranes.

Figure 4 A. Functional analysis of Clcnk2/ mice. For this type of experiment, mice are placed in metabolic cages that allow quantitative measurements of water and food intake and collection of urine and feces. Prior to the experiment, mice are often trained to get used to cage housing. Sodium excretion was measured during control period and 3 h after peritoneal injection of Furosemide (FURO), hydrochlorothiazide (HCTZ), or vehicle (mock injection).

Figure 5 NaCl transport in type B intercalated cells is rather energized by vacuolar H+-ATPase than Na+/K+-ATPase. The method for studying renal segments not directly accessible in vivo was first implemented by Burg and colleagues (51). Tubular segments are microdissected by hand without any enzymatic digestion and transferred to a perfusion chamber. They are maintained in place by two series of concentric pipettes, one for perfusion, and the other for collection. This experimental approach is technically demanding but allows using many types of different measurements. Here, the fluxes were measured by collecting fluids and analyzing ion content.

 


Related Articles:

Chloride Transport
Distal Convoluted Tubule
Regulation of Transport in the Connecting Tubule and Cortical Collecting Duct
In Vivo and Ex Vivo Analysis of Tubule Function
Proximal Nephron

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Jacques Teulon, Gabrielle Planelles, Francisco V. Sepúlveda, Olga Andrini, Stéphane Lourdel, Marc Paulais. Renal Chloride Channels in Relation to Sodium Chloride Transport. Compr Physiol 2018, 9: 301-342. doi: 10.1002/cphy.c180024