Skip to main content
NCBI home page
The Journal of General Physiology logoLink to The Journal of General Physiology
. 1995 May 1;105(5):617–641. doi: 10.1085/jgp.105.5.617

A kinetically defined Na+/H+ antiporter within a mathematical model of the rat proximal tubule

PMCID: PMC2216949  PMID: 7658195

Abstract

The luminal membrane antiporter of the proximal tubule has been represented using the kinetic formulation of E. Heinz (1978. Mechanics and Engergetics of Biological Transport. Springer-Verlag, Berlin) with the assumption of equilibrium binding and 1:1 stoichiometry. Competitive binding and transport of NH+4 is included within this model. Ion affinities and permeation velocities were selected in a least-squares fit to the kinetic parameters determined experimentally in renal membrane vesicles (Aronson, P.S., M.A. Suhm, and J. Nee. 1983. Journal of Biological Chemistry. 258:6767-6771). The modifier role of internal H+ to enhance transport beyond the expected kinetics (Aronson, P.S., J. Nee, and M. A. Suhm. 1982. Nature. 299:161-163) is represented as a velocity effect of H+ binding to a single site. This kinetic formulation of the Na+/H+ antiporter was incorporated within a model of the rat proximal tubule (Weinstein, A. M. 1994. American Journal of Physiology. 267:F237-F248) as a replacement for the representation by linear nonequilibrium thermodynamics (NET). The membrane density of the antiporter was selected to yield agreement with the rate of tubular Na+ reabsorption. Simulation of 0.5 cm of tubule predicts that the activity of the Na+/H+ antiporter is the most important force for active secretion of ammonia. Model calculations of metabolic acid-base disturbances are performed and comparison is made among antiporter representations (kinetic model, kinetic model without internal modifier, and NET formulation). It is found that the ability to sharply turn off Na+/H+ exchange in cellular alkalosis substantially eliminates the cell volume increase associated with high HCO3- conditions. In the tubule model, diminished Na+/H+ exchange in alkalosis blunts the axial decrease in luminal HCO3- and thus diminishes paracellular reabsorption of Cl-. In this way, the kinetics of the Na+/H+ antiporter could act to enhance distal delivery of Na+, Cl-, and HCO3- in acute metabolic alkalosis.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alpern R. J., Cogan M. G., Rector F. C., Jr Effect of luminal bicarbonate concentration on proximal acidification in the rat. Am J Physiol. 1982 Jul;243(1):F53–F59. doi: 10.1152/ajprenal.1982.243.1.F53. [DOI] [PubMed] [Google Scholar]
  2. Alpern R. J., Cogan M. G., Rector F. C., Jr Effects of extracellular fluid volume and plasma bicarbonate concentration on proximal acidification in the rat. J Clin Invest. 1983 Mar;71(3):736–746. doi: 10.1172/JCI110821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alpern R. J., Cogan M. G., Rector F. C., Jr Flow dependence of proximal tubular bicarbonate absorption. Am J Physiol. 1983 Oct;245(4):F478–F484. doi: 10.1152/ajprenal.1983.245.4.F478. [DOI] [PubMed] [Google Scholar]
  4. Andersen O. S. Kinetics of ion movement mediated by carriers and channels. Methods Enzymol. 1989;171:62–112. doi: 10.1016/s0076-6879(89)71007-7. [DOI] [PubMed] [Google Scholar]
  5. Aronson P. S. Kinetic properties of the plasma membrane Na+-H+ exchanger. Annu Rev Physiol. 1985;47:545–560. doi: 10.1146/annurev.ph.47.030185.002553. [DOI] [PubMed] [Google Scholar]
  6. Aronson P. S., Nee J., Suhm M. A. Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature. 1982 Sep 9;299(5879):161–163. doi: 10.1038/299161a0. [DOI] [PubMed] [Google Scholar]
  7. Aronson P. S., Suhm M. A., Nee J. Interaction of external H+ with the Na+-H+ exchanger in renal microvillus membrane vesicles. J Biol Chem. 1983 Jun 10;258(11):6767–6771. [PubMed] [Google Scholar]
  8. Bello-Reuss E. Effect of catecholamines on fluid reabsorption by the isolated proximal convoluted tubule. Am J Physiol. 1980 May;238(5):F347–F352. doi: 10.1152/ajprenal.1980.238.5.F347. [DOI] [PubMed] [Google Scholar]
  9. Biemesderfer D., Pizzonia J., Abu-Alfa A., Exner M., Reilly R., Igarashi P., Aronson P. S. NHE3: a Na+/H+ exchanger isoform of renal brush border. Am J Physiol. 1993 Nov;265(5 Pt 2):F736–F742. doi: 10.1152/ajprenal.1993.265.5.F736. [DOI] [PubMed] [Google Scholar]
  10. Boyarsky G., Ganz M. B., Cragoe E. J., Jr, Boron W. F. Intracellular-pH dependence of Na-H exchange and acid loading in quiescent and arginine vasopressin-activated mesangial cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5921–5924. doi: 10.1073/pnas.87.15.5921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chan Y. L., Biagi B., Giebisch G. Control mechanisms of bicarbonate transport across the rat proximal convoluted tubule. Am J Physiol. 1982 May;242(5):F532–F543. doi: 10.1152/ajprenal.1982.242.5.F532. [DOI] [PubMed] [Google Scholar]
  12. Cogan M. G. Angiotensin II: a powerful controller of sodium transport in the early proximal tubule. Hypertension. 1990 May;15(5):451–458. doi: 10.1161/01.hyp.15.5.451. [DOI] [PubMed] [Google Scholar]
  13. Cogan M. G., Liu F. Y. Metabolic alkalosis in the rat. Evidence that reduced glomerular filtration rather than enhanced tubular bicarbonate reabsorption is responsible for maintaining the alkalotic state. J Clin Invest. 1983 May;71(5):1141–1160. doi: 10.1172/JCI110864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Felder C. C., Campbell T., Albrecht F., Jose P. A. Dopamine inhibits Na(+)-H+ exchanger activity in renal BBMV by stimulation of adenylate cyclase. Am J Physiol. 1990 Aug;259(2 Pt 2):F297–F303. doi: 10.1152/ajprenal.1990.259.2.F297. [DOI] [PubMed] [Google Scholar]
  15. Gennari F. J., Helmle-Kolb C., Murer H. Influence of extracellular pH and perfusion rate on Na+/H+ exchange in cultured opossum kidney cells. Pflugers Arch. 1992 Feb;420(2):153–158. doi: 10.1007/BF00374984. [DOI] [PubMed] [Google Scholar]
  16. Grinstein S., Cohen S., Rothstein A. Cytoplasmic pH regulation in thymic lymphocytes by an amiloride-sensitive Na+/H+ antiport. J Gen Physiol. 1984 Mar;83(3):341–369. doi: 10.1085/jgp.83.3.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grinstein S., Rothstein A. Mechanisms of regulation of the Na+/H+ exchanger. J Membr Biol. 1986;90(1):1–12. doi: 10.1007/BF01869680. [DOI] [PubMed] [Google Scholar]
  18. Harris P. J., Navar L. G. Tubular transport responses to angiotensin. Am J Physiol. 1985 May;248(5 Pt 2):F621–F630. doi: 10.1152/ajprenal.1985.248.5.F621. [DOI] [PubMed] [Google Scholar]
  19. Kinsella J. L., Aronson P. S. Determination of the coupling ratio for Na+ -H+ exchange in renal microvillus membrane vesicles. Biochim Biophys Acta. 1982 Jul 14;689(1):161–164. doi: 10.1016/0005-2736(82)90200-0. [DOI] [PubMed] [Google Scholar]
  20. Kinsella J. L., Aronson P. S. Interaction of NH4+ and Li+ with the renal microvillus membrane Na+-H+ exchanger. Am J Physiol. 1981 Nov;241(5):C220–C226. doi: 10.1152/ajpcell.1981.241.5.C220. [DOI] [PubMed] [Google Scholar]
  21. Kinsella J. L., Aronson P. S. Properties of the Na+-H+ exchanger in renal microvillus membrane vesicles. Am J Physiol. 1980 Jun;238(6):F461–F469. doi: 10.1152/ajprenal.1980.238.6.F461. [DOI] [PubMed] [Google Scholar]
  22. Kinsella J. L., Cujdik T., Sacktor B. Kinetic studies on the stimulation of Na+-H+ exchange activity in renal brush border membranes isolated from thyroid hormone-treated rats. J Membr Biol. 1986;91(2):183–191. doi: 10.1007/BF01925795. [DOI] [PubMed] [Google Scholar]
  23. Liu F. Y., Cogan M. G. Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule. Modes of action, mechanism, and kinetics. J Clin Invest. 1988 Aug;82(2):601–607. doi: 10.1172/JCI113638. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lucci M. S., Warnock D. G. Effects of anion-transport inhibitors on NaCl reabsorption in the rat superficial proximal convoluted tubule. J Clin Invest. 1979 Aug;64(2):570–579. doi: 10.1172/JCI109495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maddox D. A., Fortin S. M., Tartini A., Barnes W. D., Gennari F. J. Effect of acute changes in glomerular filtration rate on Na+/H+ exchange in rat renal cortex. J Clin Invest. 1992 Apr;89(4):1296–1303. doi: 10.1172/JCI115715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maddox D. A., Gennari F. J. Load dependence of proximal tubular bicarbonate reabsorption in chronic metabolic alkalosis in the rat. J Clin Invest. 1986 Mar;77(3):709–716. doi: 10.1172/JCI112365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miller R. T., Pollock A. S. Modification of the internal pH sensitivity of the Na+/H+ antiporter by parathyroid hormone in a cultured renal cell line. J Biol Chem. 1987 Jul 5;262(19):9115–9120. [PubMed] [Google Scholar]
  28. Moolenaar W. H., Tsien R. Y., van der Saag P. T., de Laat S. W. Na+/H+ exchange and cytoplasmic pH in the action of growth factors in human fibroblasts. Nature. 1983 Aug 18;304(5927):645–648. doi: 10.1038/304645a0. [DOI] [PubMed] [Google Scholar]
  29. Murer H., Hopfer U., Kinne R. Sodium/proton antiport in brush-border-membrane vesicles isolated from rat small intestine and kidney. Biochem J. 1976 Mar 15;154(3):597–604. [PMC free article] [PubMed] [Google Scholar]
  30. Nord E. P., Goldfarb D., Mikhail N., Moradeshagi P., Hafezi A., Vaystub S., Cragoe E. J., Jr, Fine L. G. Characteristics of the Na+-H+ antiporter in the intact renal proximal tubular cell. Am J Physiol. 1986 Mar;250(3 Pt 2):F539–F550. doi: 10.1152/ajprenal.1986.250.3.F539. [DOI] [PubMed] [Google Scholar]
  31. Orlowski J. Heterologous expression and functional properties of amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the rat Na/H exchanger. J Biol Chem. 1993 Aug 5;268(22):16369–16377. [PubMed] [Google Scholar]
  32. Orlowski J., Kandasamy R. A., Shull G. E. Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem. 1992 May 5;267(13):9331–9339. [PubMed] [Google Scholar]
  33. Otsu K., Kinsella J. L., Heller P., Froehlich J. P. Sodium dependence of the Na(+)-H+ exchanger in the pre-steady state. Implications for the exchange mechanism. J Biol Chem. 1993 Feb 15;268(5):3184–3193. [PubMed] [Google Scholar]
  34. Otsu K., Kinsella J. L., Koh E., Froehlich J. P. Proton dependence of the partial reactions of the sodium-proton exchanger in renal brush border membranes. J Biol Chem. 1992 Apr 25;267(12):8089–8096. [PubMed] [Google Scholar]
  35. Otsu K., Kinsella J., Sacktor B., Froehlich J. P. Transient state kinetic evidence for an oligomer in the mechanism of Na+-H+ exchange. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4818–4822. doi: 10.1073/pnas.86.13.4818. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Parent L., Supplisson S., Loo D. D., Wright E. M. Electrogenic properties of the cloned Na+/glucose cotransporter: II. A transport model under nonrapid equilibrium conditions. J Membr Biol. 1992 Jan;125(1):63–79. doi: 10.1007/BF00235798. [DOI] [PubMed] [Google Scholar]
  37. Paris S., Pouysségur J. Growth factors activate the Na+/H+ antiporter in quiescent fibroblasts by increasing its affinity for intracellular H+. J Biol Chem. 1984 Sep 10;259(17):10989–10994. [PubMed] [Google Scholar]
  38. Preisig P. A. Luminal flow rate regulates proximal tubule H-HCO3 transporters. Am J Physiol. 1992 Jan;262(1 Pt 2):F47–F54. doi: 10.1152/ajprenal.1992.262.1.F47. [DOI] [PubMed] [Google Scholar]
  39. Preisig P. A., Rector F. C., Jr Role of Na+-H+ antiport in rat proximal tubule NaCl absorption. Am J Physiol. 1988 Sep;255(3 Pt 2):F461–F465. doi: 10.1152/ajprenal.1988.255.3.F461. [DOI] [PubMed] [Google Scholar]
  40. Restrepo D., Cho D. S., Kron M. J. Essential activation of Na(+)-H+ exchange by [H+]i in HL-60 cells. Am J Physiol. 1990 Sep;259(3 Pt 1):C490–C502. doi: 10.1152/ajpcell.1990.259.3.C490. [DOI] [PubMed] [Google Scholar]
  41. Sanders D., Hansen U. P., Gradmann D., Slayman C. L. Generalized kinetic analysis of ion-driven cotransport systems: a unified interpretation of selective ionic effects on Michaelis parameters. J Membr Biol. 1984;77(2):123–152. doi: 10.1007/BF01925862. [DOI] [PubMed] [Google Scholar]
  42. Sjaastad M. D., Wenzl E., Machen T. E. pHi dependence of Na-H exchange and H delivery in IEC-6 cells. Am J Physiol. 1992 Jan;262(1 Pt 1):C164–C170. doi: 10.1152/ajpcell.1992.262.1.C164. [DOI] [PubMed] [Google Scholar]
  43. Thomas S. R., Dagher G. A kinetic model of rat proximal tubule transport--load-dependent bicarbonate reabsorption along the tubule. Bull Math Biol. 1994 May;56(3):431–458. doi: 10.1007/BF02460466. [DOI] [PubMed] [Google Scholar]
  44. Tse C. M., Brant S. R., Walker M. S., Pouyssegur J., Donowitz M. Cloning and sequencing of a rabbit cDNA encoding an intestinal and kidney-specific Na+/H+ exchanger isoform (NHE-3). J Biol Chem. 1992 May 5;267(13):9340–9346. [PubMed] [Google Scholar]
  45. Tse C. M., Levine S. A., Yun C. H., Brant S. R., Pouyssegur J., Montrose M. H., Donowitz M. Functional characteristics of a cloned epithelial Na+/H+ exchanger (NHE3): resistance to amiloride and inhibition by protein kinase C. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9110–9114. doi: 10.1073/pnas.90.19.9110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Turner R. J. Quantitative studies of cotransport systems: models and vesicles. J Membr Biol. 1983;76(1):1–15. doi: 10.1007/BF01871450. [DOI] [PubMed] [Google Scholar]
  47. Verkman A. S., Alpern R. J. Kinetic transport model for cellular regulation of pH and solute concentration in the renal proximal tubule. Biophys J. 1987 Apr;51(4):533–546. doi: 10.1016/S0006-3495(87)83379-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Vigne P., Jean T., Barbry P., Frelin C., Fine L. G., Lazdunski M. [3H]Ethylpropylamiloride, a ligand to analyze the properties of the Na+/H+ exchange system in the membranes of normal and hypertrophied kidneys. J Biol Chem. 1985 Nov 15;260(26):14120–14125. [PubMed] [Google Scholar]
  49. Warnock D. G., Reenstra W. W., Yee V. J. Na+/H+ antiporter of brush border vesicles: studies with acridine orange uptake. Am J Physiol. 1982 Jun;242(6):F733–F739. doi: 10.1152/ajprenal.1982.242.6.F733. [DOI] [PubMed] [Google Scholar]
  50. Watson A. J., Levine S., Donowitz M., Montrose M. H. Kinetics and regulation of a polarized Na(+)-H+ exchanger from Caco-2 cells, a human intestinal cell line. Am J Physiol. 1991 Aug;261(2 Pt 1):G229–G238. doi: 10.1152/ajpgi.1991.261.2.G229. [DOI] [PubMed] [Google Scholar]
  51. Weinman E. J., Sansom S. C., Knight T. F., Senekjian H. O. Alpha and beta adrenergic agonists stimulate water absorption in the rat proximal tubule. J Membr Biol. 1982;69(2):107–111. doi: 10.1007/BF01872270. [DOI] [PubMed] [Google Scholar]
  52. Weinstein A. M. Ammonia transport in a mathematical model of rat proximal tubule. Am J Physiol. 1994 Aug;267(2 Pt 2):F237–F248. doi: 10.1152/ajprenal.1994.267.2.F237. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of General Physiology are provided here courtesy of The Rockefeller University Press

RESOURCES