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Chloride Transport

John C. Edwards

10.1002/cphy.c110027

Source: Volume 2, Issue 2, April 2012

Published online: April 2012

Full Article on Wiley Online Library



Abstract

Chloride transport along the nephron is one of the key actions of the kidney that regulates extracellular volume and blood pressure. To maintain steady state, the kidney needs to reabsorb the vast majority of the filtered load of chloride. This is accomplished by the integrated function of sequential chloride transport activities along the nephron. The detailed mechanisms of transport in each segment generate unique patterns of interactions between chloride and numerous other individual components that are transported by the kidney. Consequently, chloride transport is inextricably intertwined with that of sodium, potassium, protons, calcium, and water. These interactions not only allow for exquisitely precise regulation but also determine the particular patterns in which the system can fail in disease states. © 2012 American Physiological Society. Compr Physiol 2:1061‐1092, 2012.

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Figure 1. Figure 1.

Reabsorption of chloride along the nephron. The approximate fraction of the filtered load of chloride reabsorbed in various segments is shown (adapted from reference 229: Schwiebert. Current Topics in Membranes 1994 Academic Press, with permission).
Figure 2. Figure 2.

Profile of ratio of solute concentrations in tubule fluid to those in plasma (TF/P) (top), or transepithelial potential difference (bottom), along the proximal tubule (adapted from reference 201: Rector. Am J Physiol Renal Physiol, 1983, with permission).
Figure 3. Figure 3.

Chloride flux across proximal tubules as a function of its electrochemical driving force (meq/liter) (adapted from reference 6: Alpern. J. Clin Invest, 1985, with permission).
Figure 4. Figure 4.

Model of coupled chloride‐hydroxide and sodium‐proton exchangers in the apical membrane of proximal tubule cells supporting sodium gradient‐driven chloride absorption. The red oval represents a chloride‐hydroxide exchanger, the blue box represents the sodium proton exchanger, NHE3. Note the separately extruded protons and hydroxide combine to form water in the tubule lumen and no apical recycling mechanism is necessary.
Figure 5. Figure 5.

Mechanism of formate recycling to sustain sodium‐coupled chloride reabsorption by chloride/formate exchange across the apical membrane of proximal tubule cells. The red oval represents the sodium proton exchanger, NHE3, the blue rectangle represents a proton‐formate cotransporter, and the green hexagon represents a chloride‐formate exchanger (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).
Figure 6. Figure 6.

Mechanism of oxalate recycling to sustain sodium‐coupled chloride reabsorption by chloride/oxalate exchange across the apical membrane. The red oval represents a sodium‐sulfate cotransporter, the blue rectangle represents a sulfate‐oxalate exchanger, and the green hexagon represents the chloride‐oxalate exchanger, CFEX (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).
Figure 7. Figure 7.

Possible pathways for chloride exit across the basolateral membrane of proximal tubule cells, including a chloride channel (top), a potassium chloride cotransporter (middle), and a sodium dependent chloride bicarbonate exchanger (bottom) (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).
Figure 8. Figure 8.

Sodium chloride transport pathways in the thin ascending limb (adapted from reference 136: Kramer. Nature Clin Prac Nephrol, 2007, Nature Publishing Group, with permission).
Figure 9. Figure 9.

Chloride transport in the thick ascending limb. Sodium potassium ATPase in the basolateral membrane provides the energy for transport. NKCC2 (the target of loop diuretics) in the apical domain allows the sodium gradient to drive potassium and chloride into the cell. Potassium recycles across the apical membrane via ROMK. Chloride leaves across the basolateral membrane via the ClC‐KB/Barttin chloride channel. The lumen negative potential drives cation absorption through the paracellular pathway. Vasopressin or parathyroid hormone increase intracellular cAMP, activating the apical transporters while activation of the calcium‐sensing receptor has the opposite effect (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).
Figure 10. Figure 10.

Topology and transport modes of NKCC2 alternate splice forms. (A) C‐terminal variant Long form. (B) C‐terminal variant Short form, illustrating the replacement of the terminal 329 amino acids with a 55 amino acid segment, shown in yellow. The site of alternate version of encoded by the fourth exon is shown in red (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).
Figure 11. Figure 11.

Distribution of the various splice variants along the thick ascending limb (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).
Figure 12. Figure 12.

Differences in the kinetics of transport supported by the three exon 4 isoforms of NKCC2. The effect of varying extra cellular ion concentrations is shown for sodium (A), rubidium (B), and chloride (C). Normalized 86Rb uptake by oocytes injected with NKCC2B (red circles), NKCC2A (green triangles), or NKCC2F (blue squares) is presented. Horizontal bars at the bottom of the graphs represent the approximate range of ion concentration in the tubule lumen in the portion of the mammalian thick ascending limb in which each variant is present using the same color code (adapted from reference 71: Gimeniz. J Biol Chem, 2002, with permission)
Figure 13. Figure 13.

(A) Relative contribution of NKCC2A and NKCC2B isoforms to the tubuloglomerular feedback (TGF) response. Relative response magnitudes for the flow ranges indicated along the x‐axis are expressed as percentage of the total stop‐flow pressure response. (B) TGF responses in wild‐type mice compared with the sum of TGF responses in NKCC2B−/− and NKCC2A−/− mice. Response magnitudes for the flow ranges indicated along the x‐axis are expressed as changes in stop flow pressure (adapted from reference 36: Castorp. Am J Physiol Renal Physiol, 2008, with permission).
Figure 14. Figure 14.

Cells of the distal convoluted tubule. Models of the more proximal DCT‐1 cells and more distal DCT‐2 cells are shown. Transepithelial voltage is near zero at the beginning of the DCT and becomes progressively more lumen‐negative. Identified ion transporters include (A) the sodium proton exchanger NHE3; (B) the thiazide‐sensitive sodium chloride cotransporter, NCC; (C) the apical potassium channel, ROMK; (D) the sodium potassium ATPase; (E) a basolateral potassium channel, Kir; (F) a basolateral chloride channel, ClCK‐B; (G) a sodium proton exchanger, NHE‐1; and (H) the apical epithelial sodium channel, ENaC. In addition, apical chloride‐formate exchanger and potassium‐chloride cotransport activities are depicted (modified from reference 205: Reilly. Physiol Rev, 2000, with permission).
Figure 15. Figure 15.

Traditional model of ion transport by cells of the cortical collecting duct. The type B intercalated cell (left) carries out electroneutral bicarbonate secretion and chloride absorption, using apical anion exchanger, pendrin, and basolateral proton ATPase and chloride channel. The principal cell (center) carries out electrogenic sodium reabsorption coupled with potassium secretion, using apical sodium and potassium channels and basolateral sodium‐potassium ATPase. The type A intercalated cell (right) carries out electrogenic proton secretion, using apical proton ATPase, basolateral anion exchanger, AE1, and basolateral chloride exit mechanisms including a chloride channel and a potassium‐chloride contransporter, KCC4. Lumen‐negative potential generated by the principal cells may drive chloride absorption through the paracellular pathway.
Figure 16. Figure 16.

Revised model of sodium chloride reabsorption by the collecting duct. The principal cells and type A intercalated cells are as in Figure 14. The type B intercalated cell (left) express both pendrin, a chloride‐bicarbonate exchanger, and NDCBE, a sodium‐dependent chloride‐bicarbonate exchanger in the apical membrane. The cell may carry out electroneutral bicarbonate secretion, electroneutral sodium chloride reabsorption, or a combination of the two depending on the relative activities of the two exchangers. The basolateral sodium exit pathway is undefined. There is minimal paracellular chloride movement.
Figure 17. Figure 17.

Models of sodium chloride absorption and secretion activities of the inner medullary collecting duct. Sodium chloride absorption (left) is occurs by transcellular active sodium transport and paracellular chloride movement. Sodium chloride secretion occurs via transcellular active chloride transport and paracellular sodium movement.
Figure 18. Figure 18.

Possible roles of the electrogenic chloride‐proton exchange activity of ClC‐5 in endosomes. Left: proton and electrical gradient generated by the proton ATPase drives chloride proton exchange, collapsing the electrical potential and increasing intravesicular chloride concentration. Right: the intravesicular to cytoplasmic chloride gradient immediately following endocytosis drives chloride proton exchange, acidifying the vesicle independent of the proton pump and reducing intravesicular chloride.


Figure 1.

Reabsorption of chloride along the nephron. The approximate fraction of the filtered load of chloride reabsorbed in various segments is shown (adapted from reference 229: Schwiebert. Current Topics in Membranes 1994 Academic Press, with permission).



Figure 2.

Profile of ratio of solute concentrations in tubule fluid to those in plasma (TF/P) (top), or transepithelial potential difference (bottom), along the proximal tubule (adapted from reference 201: Rector. Am J Physiol Renal Physiol, 1983, with permission).



Figure 3.

Chloride flux across proximal tubules as a function of its electrochemical driving force (meq/liter) (adapted from reference 6: Alpern. J. Clin Invest, 1985, with permission).



Figure 4.

Model of coupled chloride‐hydroxide and sodium‐proton exchangers in the apical membrane of proximal tubule cells supporting sodium gradient‐driven chloride absorption. The red oval represents a chloride‐hydroxide exchanger, the blue box represents the sodium proton exchanger, NHE3. Note the separately extruded protons and hydroxide combine to form water in the tubule lumen and no apical recycling mechanism is necessary.



Figure 5.

Mechanism of formate recycling to sustain sodium‐coupled chloride reabsorption by chloride/formate exchange across the apical membrane of proximal tubule cells. The red oval represents the sodium proton exchanger, NHE3, the blue rectangle represents a proton‐formate cotransporter, and the green hexagon represents a chloride‐formate exchanger (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).



Figure 6.

Mechanism of oxalate recycling to sustain sodium‐coupled chloride reabsorption by chloride/oxalate exchange across the apical membrane. The red oval represents a sodium‐sulfate cotransporter, the blue rectangle represents a sulfate‐oxalate exchanger, and the green hexagon represents the chloride‐oxalate exchanger, CFEX (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).



Figure 7.

Possible pathways for chloride exit across the basolateral membrane of proximal tubule cells, including a chloride channel (top), a potassium chloride cotransporter (middle), and a sodium dependent chloride bicarbonate exchanger (bottom) (modified from reference 192: Planelles. Pflugers Arch, 2004, Springer‐Verlag, with permission).



Figure 8.

Sodium chloride transport pathways in the thin ascending limb (adapted from reference 136: Kramer. Nature Clin Prac Nephrol, 2007, Nature Publishing Group, with permission).



Figure 9.

Chloride transport in the thick ascending limb. Sodium potassium ATPase in the basolateral membrane provides the energy for transport. NKCC2 (the target of loop diuretics) in the apical domain allows the sodium gradient to drive potassium and chloride into the cell. Potassium recycles across the apical membrane via ROMK. Chloride leaves across the basolateral membrane via the ClC‐KB/Barttin chloride channel. The lumen negative potential drives cation absorption through the paracellular pathway. Vasopressin or parathyroid hormone increase intracellular cAMP, activating the apical transporters while activation of the calcium‐sensing receptor has the opposite effect (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).



Figure 10.

Topology and transport modes of NKCC2 alternate splice forms. (A) C‐terminal variant Long form. (B) C‐terminal variant Short form, illustrating the replacement of the terminal 329 amino acids with a 55 amino acid segment, shown in yellow. The site of alternate version of encoded by the fourth exon is shown in red (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).



Figure 11.

Distribution of the various splice variants along the thick ascending limb (adapted from reference 64: Gamba. Pflugers Arch, 2009, Springer‐Verlag, with permission).



Figure 12.

Differences in the kinetics of transport supported by the three exon 4 isoforms of NKCC2. The effect of varying extra cellular ion concentrations is shown for sodium (A), rubidium (B), and chloride (C). Normalized 86Rb uptake by oocytes injected with NKCC2B (red circles), NKCC2A (green triangles), or NKCC2F (blue squares) is presented. Horizontal bars at the bottom of the graphs represent the approximate range of ion concentration in the tubule lumen in the portion of the mammalian thick ascending limb in which each variant is present using the same color code (adapted from reference 71: Gimeniz. J Biol Chem, 2002, with permission)



Figure 13.

(A) Relative contribution of NKCC2A and NKCC2B isoforms to the tubuloglomerular feedback (TGF) response. Relative response magnitudes for the flow ranges indicated along the x‐axis are expressed as percentage of the total stop‐flow pressure response. (B) TGF responses in wild‐type mice compared with the sum of TGF responses in NKCC2B−/− and NKCC2A−/− mice. Response magnitudes for the flow ranges indicated along the x‐axis are expressed as changes in stop flow pressure (adapted from reference 36: Castorp. Am J Physiol Renal Physiol, 2008, with permission).



Figure 14.

Cells of the distal convoluted tubule. Models of the more proximal DCT‐1 cells and more distal DCT‐2 cells are shown. Transepithelial voltage is near zero at the beginning of the DCT and becomes progressively more lumen‐negative. Identified ion transporters include (A) the sodium proton exchanger NHE3; (B) the thiazide‐sensitive sodium chloride cotransporter, NCC; (C) the apical potassium channel, ROMK; (D) the sodium potassium ATPase; (E) a basolateral potassium channel, Kir; (F) a basolateral chloride channel, ClCK‐B; (G) a sodium proton exchanger, NHE‐1; and (H) the apical epithelial sodium channel, ENaC. In addition, apical chloride‐formate exchanger and potassium‐chloride cotransport activities are depicted (modified from reference 205: Reilly. Physiol Rev, 2000, with permission).



Figure 15.

Traditional model of ion transport by cells of the cortical collecting duct. The type B intercalated cell (left) carries out electroneutral bicarbonate secretion and chloride absorption, using apical anion exchanger, pendrin, and basolateral proton ATPase and chloride channel. The principal cell (center) carries out electrogenic sodium reabsorption coupled with potassium secretion, using apical sodium and potassium channels and basolateral sodium‐potassium ATPase. The type A intercalated cell (right) carries out electrogenic proton secretion, using apical proton ATPase, basolateral anion exchanger, AE1, and basolateral chloride exit mechanisms including a chloride channel and a potassium‐chloride contransporter, KCC4. Lumen‐negative potential generated by the principal cells may drive chloride absorption through the paracellular pathway.



Figure 16.

Revised model of sodium chloride reabsorption by the collecting duct. The principal cells and type A intercalated cells are as in Figure 14. The type B intercalated cell (left) express both pendrin, a chloride‐bicarbonate exchanger, and NDCBE, a sodium‐dependent chloride‐bicarbonate exchanger in the apical membrane. The cell may carry out electroneutral bicarbonate secretion, electroneutral sodium chloride reabsorption, or a combination of the two depending on the relative activities of the two exchangers. The basolateral sodium exit pathway is undefined. There is minimal paracellular chloride movement.



Figure 17.

Models of sodium chloride absorption and secretion activities of the inner medullary collecting duct. Sodium chloride absorption (left) is occurs by transcellular active sodium transport and paracellular chloride movement. Sodium chloride secretion occurs via transcellular active chloride transport and paracellular sodium movement.



Figure 18.

Possible roles of the electrogenic chloride‐proton exchange activity of ClC‐5 in endosomes. Left: proton and electrical gradient generated by the proton ATPase drives chloride proton exchange, collapsing the electrical potential and increasing intravesicular chloride concentration. Right: the intravesicular to cytoplasmic chloride gradient immediately following endocytosis drives chloride proton exchange, acidifying the vesicle independent of the proton pump and reducing intravesicular chloride.

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Article Title: Chloride Transport
 

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John C. Edwards. Chloride Transport. Compr Physiol 2012, 2: 1061-1092. doi: 10.1002/cphy.c110027