HCO 3 − 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, M. 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 CO₂ (net${HCO}_3^{-}$ flux,J_tCO2) was measured in the presence of 10 μM Schering 28080 (SCH, inhibitor of gastric H⁺-K⁺-ATPase) or 50 μM diethylestilbestrol (DES, inhibitor of H⁺-ATPase) in both mutant and wild-type (WT) animals. In CCD,J_tCO2increased in NHE-3 mutant mice (3.42 ± 0.28 in WT to 5.71 ± 0.39 pmol ⋅ min⁻¹ ⋅ mm tubule⁻¹ in mutants,P < 0.001). The SCH-sensitive net${HCO}_3^{-}$ flux remained unchanged, whereas the DES-sensitive ${HCO}_3^{-}$ flux increased in the CCD of NHE-3 mutant animals. In OMCD,J_tCO2increased 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.