Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger

Abstract

NHE3 is one of five plasma membrane Na+/H+ exchangers1,2,3 and is encoded by the mouse gene Slc9a3 . It is expressed on apical membranes of renal proximal tubule4,5 and intestinal epithelial cells6,7 and is thought to play a major role in NaCl and HCO3 absorption4,5,6,7,8,9,10. As the distribution of NHE3 overlaps with that of the NHE2 isoform in kidney7,11 and intestine7,12,13, the function and relative importance of NHE3 in vivo is unclear. To analyse its physiological functions, we generated mice lacking NHE3 function. Homozygous mutant (Slc9a3–/–) mice survive, but they have slight diarrhoea and blood analysis revealed that they are mildly acidotic. HCO3 and fluid absorption are sharply reduced in proximal convoluted tubules, blood pressure is reduced and there is a severe absorptive defect in the intestine. Thus, compensatory mechanisms must limit gross perturbations of electrolyte and acid-base balance. Plasma aldosterone is increased in NHE3-deficient mice, and expression of both renin and the AE1 (Slc4a1) Cl/HCO3 exchanger mRNAs are induced in kidney. In the colon, epithelial Na+ channel activity is increased and colonic H+,K+-ATPase mRNA is massively induced. These data show that NHE3 is the major absorptive Na+/H+ exchanger in kidney and intestine, and that lack of the exchanger impairs acid-base balance and Na+-fluid volume homeostasis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted disruption of the Slc9a3 gene.
Figure 2: Analysis of proximal tubule fluid and bicarbonate absorption and blood pressure in adult Slc9a3+/+ and Slc9a3–/– mice.
Figure 3: Intestinal phenotype.
Figure 4: Compensatory mechanisms.

Similar content being viewed by others

References

  1. Orlowski, J., Kandasamy, R.A. & Shull, G.E. Molecular cloning of putative members of the Na/H exchanger gene family. J. Biol. Chem. 267, 9331–9339 (1992).

    CAS  Google Scholar 

  2. 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. 267, 9340 –9346 (1992).

    CAS  Google Scholar 

  3. Orlowski, J. & Grinstein, S. Na+/H+ exchangers of mammalian cells. J. Biol. Chem. 272, 22373–22376 (1997).

    Article  CAS  Google Scholar 

  4. Biemesderfer, D. et al. NHE3: a Na+/H+ exchanger isoform of renal brush border. Am. J. Physiol. 265, F736– F742 (1993).

    CAS  Google Scholar 

  5. Amemiya, M. et al. Expression of NHE3 in the apical membrane of rat renal proximal tubule and thick ascending limb. Kidney Int. 48, 1206 –1215 (1995).

    Article  CAS  Google Scholar 

  6. Bookstein, C. et al. Na+/H+ exchangers, NHE-1 and NHE-3, of rat intestine. Expression and localization. J. Clin. Invest. 93, 106–113 (1994).

    Article  CAS  Google Scholar 

  7. Hoogerwerf, W.A. et al. NHE2 and NHE3 are human and rabbit intestinal brush-border proteins. Am. J. Physiol. 270, G29–G41 (1996).

    CAS  Google Scholar 

  8. Wu, M.-S., Biemesderfer, D., Giebisch, G. & Aronson, P.S. Role of NHE3 in mediating renal brush border Na+-H+ exchange. Adaptation to metabolic acidosis. J. Biol. Chem. 271 , 32749–32752 (1996).

    Article  CAS  Google Scholar 

  9. Aronson, P.S. & Giebisch, G. Mechanisms of chloride transport in the proximal tubule. Am. J. Physiol. 273, F179–F192 (1997).

    Article  CAS  Google Scholar 

  10. Yun, C.H.C. et al. Glucocorticoid stimulation of ileal Na+ absorptive cell brush border Na+/H+ exchange and association with an increase in message for NHE-3, an epithelial Na+/H+ exchanger isoform. J. Biol. Chem. 268, 206–211 (1993).

    CAS  Google Scholar 

  11. Azuma, K.K. et al. Renal Na+/H+ exchanger isoforms and their regulation by thyroid hormone. Am. J. Physiol. 270, C585–C592 (1996).

    Article  CAS  Google Scholar 

  12. Bookstein, C. et al. Tissue distribution of Na+/H+ exchanger isoforms NHE2 and NHE4 in rat intestine and kidney. Am. J. Physiol. 273, C1496–C1505 (1997).

    Article  CAS  Google Scholar 

  13. Dudeja, P.K. et al. Intestinal distribution of human Na+/H+ exchanger isoforms NHE-1, NHE-2, and NHE-3 mRNA. Am. J. Physiol. 271, G483–G493 (1996).

    CAS  Google Scholar 

  14. Wakabayashi, S., Fafournoux, P., Sardet, C. & Pouyssegur, J. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls H+-sensing. Proc. Natl Acad. Sci. USA. 89, 2424– 2428 (1992).

    Article  CAS  Google Scholar 

  15. Fafournoux, P., Noel, J. & Pouyssegur, J. Evidence that Na+/H+ exchanger isoforms NHE1 and NHE3 exist as stable dimers in membranes with a high degree of specificity for homodimers. J. Biol. Chem. 269, 2589–2596 (1994).

    CAS  Google Scholar 

  16. Simon, D.B. et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet. 13, 183–188 ( 1996).

    Article  CAS  Google Scholar 

  17. Simon, D.B. et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nature Genet. 12, 24–30 (1996).

    Article  CAS  Google Scholar 

  18. Chang, S.S. et al. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nature Genet. 12, 248–253 ( 1996).

    Article  CAS  Google Scholar 

  19. Guyton, A.C. Blood pressure control -- special role of the kidneys and body fluids. Science 252, 1813–1816 ( 1991).

    Article  CAS  Google Scholar 

  20. Lifton, R.P. Molecular genetics of human blood pressure variation. Science 272, 676–680 (1996).

    Article  CAS  Google Scholar 

  21. Teixeira Da Silva, J.C., Jr., Perrone, R.D., Johns, C.A. & Madias, N.E. Rat kidney band 3 mRNA modulation in chronic respiratory acidosis. Am. J. Physiol. 260, F204–F209 (1991).

    CAS  Google Scholar 

  22. Meneton, P. et al. Increased sensitivity to K+ deprivation in colonic H,K-ATPase-deficient mice. J. Clin. Invest. 101, 536– 542 (1998).

    Article  CAS  Google Scholar 

  23. Kaunitz, J.D., Barrett, K.E. & McRoberts, J.A. Electrolyte secretion and absorption: small intestine and colon. in Textbook of Gastroenterology, (ed. Yamada, T.) 326–361 (JB Lippincott Company, Philadelphia, 1995).

    Google Scholar 

  24. Powell, D.W. Approach to the patient with diarrhea. in Textbook of Gastroenterology, (ed. Yamada, T.) 813–863 (JB Lippincott Company, Philadelphia, 1995).

    Google Scholar 

  25. Schultheis, P.J. et al. Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J. Clin. Invest. 101, 1243–1253 (1998).

    Article  CAS  Google Scholar 

  26. Fell, J.M., Miller, M.P., Finkel, Y. & Booth, I.W. Congenital sodium diarrhea with a partial defect in jejunal brush border membrane sodium transport, normal rectal transport, and resolving diarrhea. J. Pediatr. Gastroenterol. Nutr. 15, 112–116 ( 1992).

    Article  CAS  Google Scholar 

  27. Krege, J.H., Hodgin, J.B., Hagaman, J.R. & Smithies, O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25, 1111–1115 (1995).

    Article  CAS  Google Scholar 

  28. Lorenz, J.N. & Robbins, J. Measurement of intraventricular pressure and cardiac performance in the intact closed-chest anesthetized mouse . Am. J. Physiol. 272, H1137– H1146 (1997).

    CAS  Google Scholar 

  29. Wang, T. & Chan, Y.L. Mechanism of angiotensin II action on proximal tubule transport. J. Pharmacol. Exper. Ther. 252, 689–695 (1990).

    CAS  Google Scholar 

  30. Clarke, L.L. & Harline, M.C. CFTR is required for cAMP inhibition of intestinal Na+ absorption in a cystic fibrosis mouse model . Am. J. Physiol. 270, G259– G267 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants DK50594, HL41496, DK48816, DK46789, DK33793 and DK17433.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gary E. Shull.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schultheis, P., Clarke, L., Meneton, P. et al. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 19, 282–285 (1998). https://doi.org/10.1038/969

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/969

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing