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Glucose Transport in the Renal Proximal Tubule

Mel Silverman, R. James Turner

10.1002/cphy.cp080243

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 General Characteristics
1.1 Glucose Handling by the Whole Kidney
1.2 Tubular Site of Reabsorption
1.3 D‐Glucose Handling by the Intact Proximal Tubule
2 Current Understanding of the Mechanism of Glucose Reabsorption
2.1 Components of the Reabsorptive Mechanism
2.2 Energetics: Gradient Hypothesis
2.3 Na+ Dependence of Luminal versus Basolateral D‐glucose Transport
2.4 Kinetics and Stoichiometry
2.5 Systematics of D‐Glucose Reabsorption at the Cellular and Tubular Levels
2.6 Specificity Characteristics
3 Abnormalities of Glucose Reabsorption in the Renal Tubule
3.1 Renal Glycosuria
3.2 Fanconi's Syndrome
3.3 Specific Defects of D‐Glucose Transport
4 Molecular Characterization of the Components of the D‐Glucose Reabsorptive Pathway Across the Renal Proximal Tubule
4.1 The Luminal Na+‐Dependent D‐Glucose Carrier
4.2 The Basolateral Na+‐Independent D‐Glucose Carrier
5 Molecular Mechanism of Operation of the Na+‐Dependent D‐Glucose Transporter
6 Conclusion
Figure 1. Figure 1.

Schematic representation of typical titration curve for renal D‐glucose reabsorption in man.
Figure 2. Figure 2.

Top: schematic of cytoplasmic carrier mechanism. C, carrier; G, substrate; M, membrane. I and II indicate proposed sites of assumed chemical reactions, e.g., phosphorylation and dephosphorylation, at luminal and contraluminal cell surfaces. Bottom: gradients for substrate within membrane and cytoplasmic domains.

From Wilbrandt 117
Figure 3. Figure 3.

Schematic of membrane carrier mechanism. Carrier substance, C, is present in luminal membrane of proximal tubular cells in fixed and limited amount. At exterior surface of membrane, C combines reversibly with glucose, G, present in tubular fluid, to form complex GC within membrane. GC then migrates to cytoplasmic surface of luminal membrane, where it dissociates so that glucose is delivered into cytoplasm of tubular cell, and membrane carrier, G, returns to exterior surface to accept another glucose molecule.

From Pitts 66
Figure 4. Figure 4.

Schematic of reabsorptive pathway for D‐glucose across proximal tubule epithelium. G, luminal or brush border carrier mechanism; G', basolateral D‐glucose transporter.
Figure 5. Figure 5.

Specially prepared 46 high‐resolution S.E.M. exposing apical region of proximal tubular cell from rat kidney. Urine surface is at top. Note vesicle‐like structures emerging from crypt regions between microvilli that probably represent origins of pinocytotic vesicles. As discussed in text, the entire cell is filled with small mitochondria that reach well into cytoskeletal region under mucosal surface.

Courtesy of Mr. P. Lea and Dr. M. Hollenberg
Figure 6. Figure 6.

Schematic of components of tubular reabsorptive mechanism for D‐glucose illustrating features of secondary‐active transport system. More details of G (luminal) and G' (contraluminal) D‐glucose carriers are shown here than in Figure 4. Active extrusion of Na+ across basolateral membrane by Na+,K+‐dependent ATPase creates a transmucosal electrochemical potential gradient for Na+ that energizes D‐glucose entry into the cell via coupling of Na+ and D‐glucose at G carrier level.
Figure 7. Figure 7.

Illustration emphasizing integrated aspects of transport systems in renal proximal tubule. Various ion symport and antiport systems are indicated: U (urate), S (sugars), a‐a (amino acid), L (lactate). Tight junctions representing “fences” between intercellular and luminal spaces represented by “stop” signs. Energetic coupling between antiluminal Na+‐ and K+‐ATPase and luminal transport is conceptually indicated by suggesting that height of “slide” is determined by ATP hydrolysis at cytoplasmic surface of ATPase.

From Silverman and Turner 94
Figure 8. Figure 8.

Experimental “dissociation” of Na+ chemical gradient (GRAD Na) and anion diffusion potential ΔψSCN driving forces of D‐glucose uptake into brush border vesicles from dog kidney. Concentration of D‐glucose and unspecific marker L‐glucose was 1 mM. Mannitol (100 mM) was present both inside and outside; other additions shown in inset. Experimental conditions: a: D‐glucose uptake in presence of both GRAD Na and ΔψSCN; b: D‐glucose uptake with ΔψSCN removed; and c: D‐glucose uptake in absence of ΔψSCN and GRAD Na. Experimental details are described in text. VAL, valinomycin; NIG, nigericin.

From Silverman 84
Figure 9. Figure 9.

Kinetics of Na+‐dependent stereospecific component of initial (4 s) D‐glucose flux into rabbit outer cortical and outer medullary brush border membrane vesicles measured under zero trans Na+ and glucose conditions at 17°C. Incubation medium contained labeled glucose and 40 mM NaCl or 40 mM choline chloride (final concentrations). Uptakes observed in presence of choline were subtracted from those found in presence of Na+ to obtain Na+‐dependent component of D‐glucose flux. Glucose concentration ranges shown are 0.2–20 mM for outer cortical preparation and 0.1–8 mM for outer medullary preparation. Least‐squares fits yield Km = 5.7 ± 1.3 mM, Vmax = 9.7 ± 1.7 nmol · min−1 · mg protein−1, r = 0.984 for outer cortex; Km = 0.34 ± 0.05 mM, Vmax = 4.1 ± 0.3 nmol · min−1 · mg protein−1, r = 0.993 for outer medulla.

From Turner and Moran 102
Figure 10. Figure 10.

Schematic summarizing luminal and contraluminal distribution of different sugar‐carrier mechanisms in renal proximal tubule. Details of localization (i.e., convoluted or straight segments), specificity, and kinetic characteristics are given in text. , Na+–D‐glucose transporter with 1:1 Na+:D‐glucose stoichiometry; , Na+–D‐glucose transporter with 2:1 Na+:D‐glucose stoichiometry; M, mannose transporter; Myo, myoinositol transporter, G', Na+‐independent D‐glucose transporter; Myo', basolateral myoinositol carrier.

From Silverman 86
Figure 11. Figure 11.

Minimal (upper) and optimal (lower) interacting sites between pyranoside and brush border membrane G carrier from exterior surface. Noncovalent interaction (H bond) is tentatively assigned as indicated.

From Silverman 82
Figure 12. Figure 12.

a: chemical structure of phlorizin and its aglycone. b: space‐filling molecular model of phlorizin.

From Silverman 82
Figure 13. Figure 13.

Illustration of minimal specificity requirements for pyranose interaction with portion of G' exposed at exterior (blood) side of basolateral membrane. Tentative noncovalent interaction (H bond) between hydroxyl groups at C1 and C2 and receptor site is indicated.

From Silverman 83
Figure 14. Figure 14.

Schematic of inherited tubular disorders indicating possible sites of plasma membrane dysfunction. Types I and II defects are defined in text. T.J., tight junction; X, potential molecular lesion; BBM, brush border membrane; ALM, antiluminal membrane.

From Silverman 94
Figure 15. Figure 15.

Artist's view of Na+–glucose cotransport corresponding to preferred, ordered pathway shown in kinetic model in Figure 16 (solid line).

From Hopfer 32
Figure 16. Figure 16.

Kinetic model of Na+‐glucose cotransport with 1:1 stoichiometry. Solid line indicates preferred pathway or binding. Model is written as net transport under physiological conditions; however, all steps are assumed to be freely reversible. In Cleland's nomenclature, the mechanism is iso‐random bi–bi with preference for a particular ordered transport sequence and Na+ binding on the inside (solid line) at high [Na+].

From Hopfer and Groseclose 33


Figure 1.

Schematic representation of typical titration curve for renal D‐glucose reabsorption in man.



Figure 2.

Top: schematic of cytoplasmic carrier mechanism. C, carrier; G, substrate; M, membrane. I and II indicate proposed sites of assumed chemical reactions, e.g., phosphorylation and dephosphorylation, at luminal and contraluminal cell surfaces. Bottom: gradients for substrate within membrane and cytoplasmic domains.

From Wilbrandt 117


Figure 3.

Schematic of membrane carrier mechanism. Carrier substance, C, is present in luminal membrane of proximal tubular cells in fixed and limited amount. At exterior surface of membrane, C combines reversibly with glucose, G, present in tubular fluid, to form complex GC within membrane. GC then migrates to cytoplasmic surface of luminal membrane, where it dissociates so that glucose is delivered into cytoplasm of tubular cell, and membrane carrier, G, returns to exterior surface to accept another glucose molecule.

From Pitts 66


Figure 4.

Schematic of reabsorptive pathway for D‐glucose across proximal tubule epithelium. G, luminal or brush border carrier mechanism; G', basolateral D‐glucose transporter.



Figure 5.

Specially prepared 46 high‐resolution S.E.M. exposing apical region of proximal tubular cell from rat kidney. Urine surface is at top. Note vesicle‐like structures emerging from crypt regions between microvilli that probably represent origins of pinocytotic vesicles. As discussed in text, the entire cell is filled with small mitochondria that reach well into cytoskeletal region under mucosal surface.

Courtesy of Mr. P. Lea and Dr. M. Hollenberg


Figure 6.

Schematic of components of tubular reabsorptive mechanism for D‐glucose illustrating features of secondary‐active transport system. More details of G (luminal) and G' (contraluminal) D‐glucose carriers are shown here than in Figure 4. Active extrusion of Na+ across basolateral membrane by Na+,K+‐dependent ATPase creates a transmucosal electrochemical potential gradient for Na+ that energizes D‐glucose entry into the cell via coupling of Na+ and D‐glucose at G carrier level.



Figure 7.

Illustration emphasizing integrated aspects of transport systems in renal proximal tubule. Various ion symport and antiport systems are indicated: U (urate), S (sugars), a‐a (amino acid), L (lactate). Tight junctions representing “fences” between intercellular and luminal spaces represented by “stop” signs. Energetic coupling between antiluminal Na+‐ and K+‐ATPase and luminal transport is conceptually indicated by suggesting that height of “slide” is determined by ATP hydrolysis at cytoplasmic surface of ATPase.

From Silverman and Turner 94


Figure 8.

Experimental “dissociation” of Na+ chemical gradient (GRAD Na) and anion diffusion potential ΔψSCN driving forces of D‐glucose uptake into brush border vesicles from dog kidney. Concentration of D‐glucose and unspecific marker L‐glucose was 1 mM. Mannitol (100 mM) was present both inside and outside; other additions shown in inset. Experimental conditions: a: D‐glucose uptake in presence of both GRAD Na and ΔψSCN; b: D‐glucose uptake with ΔψSCN removed; and c: D‐glucose uptake in absence of ΔψSCN and GRAD Na. Experimental details are described in text. VAL, valinomycin; NIG, nigericin.

From Silverman 84


Figure 9.

Kinetics of Na+‐dependent stereospecific component of initial (4 s) D‐glucose flux into rabbit outer cortical and outer medullary brush border membrane vesicles measured under zero trans Na+ and glucose conditions at 17°C. Incubation medium contained labeled glucose and 40 mM NaCl or 40 mM choline chloride (final concentrations). Uptakes observed in presence of choline were subtracted from those found in presence of Na+ to obtain Na+‐dependent component of D‐glucose flux. Glucose concentration ranges shown are 0.2–20 mM for outer cortical preparation and 0.1–8 mM for outer medullary preparation. Least‐squares fits yield Km = 5.7 ± 1.3 mM, Vmax = 9.7 ± 1.7 nmol · min−1 · mg protein−1, r = 0.984 for outer cortex; Km = 0.34 ± 0.05 mM, Vmax = 4.1 ± 0.3 nmol · min−1 · mg protein−1, r = 0.993 for outer medulla.

From Turner and Moran 102


Figure 10.

Schematic summarizing luminal and contraluminal distribution of different sugar‐carrier mechanisms in renal proximal tubule. Details of localization (i.e., convoluted or straight segments), specificity, and kinetic characteristics are given in text. , Na+–D‐glucose transporter with 1:1 Na+:D‐glucose stoichiometry; , Na+–D‐glucose transporter with 2:1 Na+:D‐glucose stoichiometry; M, mannose transporter; Myo, myoinositol transporter, G', Na+‐independent D‐glucose transporter; Myo', basolateral myoinositol carrier.

From Silverman 86


Figure 11.

Minimal (upper) and optimal (lower) interacting sites between pyranoside and brush border membrane G carrier from exterior surface. Noncovalent interaction (H bond) is tentatively assigned as indicated.

From Silverman 82


Figure 12.

a: chemical structure of phlorizin and its aglycone. b: space‐filling molecular model of phlorizin.

From Silverman 82


Figure 13.

Illustration of minimal specificity requirements for pyranose interaction with portion of G' exposed at exterior (blood) side of basolateral membrane. Tentative noncovalent interaction (H bond) between hydroxyl groups at C1 and C2 and receptor site is indicated.

From Silverman 83


Figure 14.

Schematic of inherited tubular disorders indicating possible sites of plasma membrane dysfunction. Types I and II defects are defined in text. T.J., tight junction; X, potential molecular lesion; BBM, brush border membrane; ALM, antiluminal membrane.

From Silverman 94


Figure 15.

Artist's view of Na+–glucose cotransport corresponding to preferred, ordered pathway shown in kinetic model in Figure 16 (solid line).

From Hopfer 32


Figure 16.

Kinetic model of Na+‐glucose cotransport with 1:1 stoichiometry. Solid line indicates preferred pathway or binding. Model is written as net transport under physiological conditions; however, all steps are assumed to be freely reversible. In Cleland's nomenclature, the mechanism is iso‐random bi–bi with preference for a particular ordered transport sequence and Na+ binding on the inside (solid line) at high [Na+].

From Hopfer and Groseclose 33
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Article Title: Glucose Transport in the Renal Proximal Tubule
 

How to Cite

Mel Silverman, R. James Turner. Glucose Transport in the Renal Proximal Tubule. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 2017-2038. First published in print 1992. doi: 10.1002/cphy.cp080243