HCO3- reabsorption in renal collecting duct of NHE-3- deficient mouse:: a compensatory response

Mice with a targeted disruption of Na(+)/H(+) exchanger NHE-3 gene show significant reduction in HCO(3)(-) reabsorption in proximal tubule, consistent with the absence of NHE-3. Serum HCO(3)(-), however, is only mildly decreased (P. Schulties, L. L. Clarke, P. Meneton, M. L. Miller, ill. Soleimani, L. R. Gawenis, T. M. Riddle, J. J. Duffy, T Doetschman, T. Wang, G. Giebisch, P. S. Aronson, J. N. Lorenz, and G. E. Shull. Nature Genet. 19: 282-285, 1998), indicating possible adaptive upregulation of HCO(3)(-)absorbing transporters in collecting duct of NHE-3-deficient (NHE-3 -/-) mice. Cortical collecting duct (CCD) and outer medullary collecting duct (OMCD) were perfused, and total CO(2) (net HCO(3)(-) flux, J(tCO2)) was measured in the presence of 10 mu M Schering 28080 (SCH, inhibitor of gastric H(+)-K(+)-ATPase) or 50 mu M diethylestilbestrol (DES, inhibitor of Hf-ATPase) in both mutant and wild-type (WT) animals. In CCD, J(tCO2) increased in NHE-3 mutant mice (3.42 +/- 0.28 in WT to 5.71 +/- 0.39 pmol min-l mm tubule-l in mutants, P < 0.001). The SCH-sensitive net HCO, flux remained unchanged, whereas the DES-sensitive HCO(3)(-) flux increased in the CCD of NHE-3 mutant animals. In OMCD, J(tCO2) increased in NHE-3 mutant mice (8.8 +/- 0.7 in WT to 14.2 +/- 0.6 pmol.min(-1).mm tubule-1 in mutants, P < 0.001). Both the SCH-sensitive and the DES-sensitive HCO(3)(-) fluxes increased in the OMCD of NHE-3 mutant animals. Northern hybridizations demonstrated enhanced expression of the basolateral Cl(-)/HCO(3)(-), exchanger (AE-1) mRNA in the cortex. The gastric H(+)-K(+)-ATPase mRNA showed upregulation in the medulla but not the cortex of NHE-3 mutant mice. Our results indicate that HCO(3)(-) reabsorption is enhanced in CCD and OMCD of NHE-3-deficient mice. In CCD, H(+)-ATPase, and in the OMCD, both H(+)-ATPase and gastric H(+)-K(+)-ATPase contribute to the enhanced compensatory HCO(3)(-) reabsorption in NHE-3-deficient animals.