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 inHCO3−reabsorption in proximal tubule, consistent with the absence of NHE-3. SerumHCO3−, 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 ofHCO3−-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(netHCO3−flux,JtCO2) 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,JtCO2increased in NHE-3 mutant mice (3.42 ± 0.28 in WT to 5.71 ± 0.39 pmol ⋅ min−1⋅ mm tubule−1in mutants,P< 0.001). The SCH-sensitive netHCO3−flux remained unchanged, whereas the DES-sensitive HCO3−flux increased in the CCD of NHE-3 mutant animals. In OMCD,JtCO2increased in NHE-3 mutant mice (8.8 ± 0.7 in WT to 14.2 ± 0.6 pmol ⋅ min−1⋅ mm tubule−1in mutants,P< 0.001). Both the SCH-sensitive and the DES-sensitive HCO3−fluxes increased in the OMCD of NHE-3 mutant animals. Northern hybridizations demonstrated enhanced expression of the basolateral Cl−/HCO3−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 thatHCO3−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 compensatoryHCO3−reabsorption in NHE-3-deficient animals.