Mice with a targeted disruption of Na⁺/H⁺ exchanger NHE-3 gene show significant reduction in HCO₃ reabsorption in proximal tubule, consistent with the absence of NHE-3. Serum HCO₃, 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 HCO₃-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 HCO₃ 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_tCO2 increased in NHE-3 mutant mice (3.42 ± 0.28 in WT to 5.71 ± 0.39 pmol · min¹ · mm tubule¹ in mutants, P < 0.001). The SCH-sensitive net HCO₃ flux remained unchanged, whereas the DES-sensitive HCO₃ 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 · min¹ · mm tubule¹ in 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 that HCO₃ 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 HCO₃ reabsorption in NHE-3-deficient animals.

acid-base; proton-potassium-adenosinetriphosphatase; AE-1; proton-adenosinetriphosphatase; bicarbonate reabsorption; cortical collecting duct; outer medullary collecting duct; NHE-3 knockout

This article has been cited by other articles:

				S. Watanabe, S. Tsuruoka, S. Vijayakumar, G. Fischer, Y. Zhang, A. Fujimura, Q. Al-Awqati, and G. J. Schwartz Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin Am J Physiol Renal Physiol, January 1, 2005; 288(1): F40 - F47. [Abstract] [Full Text] [PDF]

				S. Nakamura Glucose activates H+-ATPase in kidney epithelial cells Am J Physiol Cell Physiol, July 1, 2004; 287(1): C97 - C105. [Abstract] [Full Text] [PDF]

				C. Ledoussal, A. L. Woo, M. L. Miller, and G. E. Shull Loss of the NHE2 Na+/H+ exchanger has no apparent effect on diarrheal state of NHE3-deficient mice Am J Physiol Gastrointest Liver Physiol, December 1, 2001; 281(6): G1385 - G1396. [Abstract] [Full Text] [PDF]

				C. Ledoussal, J. N. Lorenz, M. L. Nieman, M. Soleimani, P. J. Schultheis, and G. E. Shull Renal salt wasting in mice lacking NHE3 Na+/H+ exchanger but not in mice lacking NHE2 Am J Physiol Renal Physiol, October 1, 2001; 281(4): F718 - F727. [Abstract] [Full Text] [PDF]

				X. Zhou, S. Nakamura, S.-L. Xia, and C. S. Wingo Increased CO2 stimulates K/Rb reabsorption mediated by H-K-ATPase in CCD of potassium-restricted rabbit Am J Physiol Renal Physiol, August 1, 2001; 281(2): F366 - F373. [Abstract] [Full Text] [PDF]

				W. Wang, T.-H. Kwon, C. Li, A. Flyvbjerg, M. A. Knepper, J. Frokiar, and S. Nielsen Altered expression of renal aquaporins and Na+ transporters in rats treated with L-type calcium blocker Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1632 - R1641. [Abstract] [Full Text] [PDF]

				J. R. Turner, E. D. Black, J. Ward, C.-M. Tse, F. A. Uchwat, H. A. Alli, M. Donowitz, J. L. Madara, and J. M. Angle Transepithelial resistance can be regulated by the intestinal brush-border Na+/H+ exchanger NHE3 Am J Physiol Cell Physiol, December 1, 2000; 279(6): C1918 - C1924. [Abstract] [Full Text] [PDF]

				G. E. Shull, M. L. Miller, and P. J. Schultheis Lessons from Genetically Engineered Animal Models. VIII. Absorption and secretion of ions in the gastrointestinal tract Am J Physiol Gastrointest Liver Physiol, February 1, 2000; 278(2): G185 - G190. [Abstract] [Full Text] [PDF]

				Z. Spicer, M. L. Miller, A. Andringa, T. M. Riddle, J. J. Duffy, T. Doetschman, and G. E. Shull Stomachs of Mice Lacking the Gastric H,K-ATPase alpha -Subunit Have Achlorhydria, Abnormal Parietal Cells, and Ciliated Metaplasia J. Biol. Chem., July 7, 2000; 275(28): 21555 - 21565. [Abstract] [Full Text] [PDF]

				S. Petrovic, Z. Spicer, T. Greeley, G. E Shull, and M. Soleimani Novel Schering and ouabain-insensitive potassium-dependent proton secretion in the mouse cortical collecting duct Am J Physiol Renal Physiol, January 1, 2002; 282(1): F133 - F143. [Abstract] [Full Text] [PDF]