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.

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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.

References

  1. 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).

  2. 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).

  3. 3

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

  4. 4

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

  5. 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).

  6. 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).

  7. 7

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

  8. 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).

  9. 9

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

  10. 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).

  11. 11

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

  12. 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).

  13. 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).

  14. 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).

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 19

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

  20. 20

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

  21. 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).

  22. 22

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

  23. 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).

  24. 24

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

  25. 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).

  26. 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).

  27. 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).

  28. 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).

  29. 29

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

  30. 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).

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Acknowledgements

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

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Correspondence to Gary E. Shull.

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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

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