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Renal Chloride Channels in Relation to Sodium Chloride Transport

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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.

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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 ().
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 (). 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 ().
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 (). 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 of Park et al., Elife 7: 2018 () 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 ().
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. ()]
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. ()].
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. ()].
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. ()]
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. ()].
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. ()]. (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. ()].
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 (), 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 ().
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 ().
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. ()].
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. ()].
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. ()].


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 ().


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 (). 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 ().


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 (). 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 of Park et al., Elife 7: 2018 () 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 ().


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. ()]


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. ()].


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. ()].


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. ()]


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. ()].


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. ()]. (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. ()].


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 (), 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 ().


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 ().


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. ()].


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. ()].


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. ()].
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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
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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