Na⁺/HCO₃^- Cotransporter NBCn2 Mediates HCO₃^- Reclamation in the Apical Membrane of Renal Proximal Tubules.

ABSTRACT: The kidney maintains systemic acid-base balance by reclaiming from the renal tubule lumen virtually all HCO₃^- filtered in glomeruli and by secreting additional H⁺ to titrate luminal buffers. For proximal tubules, which are responsible for about 80% of this activity, it is believed that HCO₃^- reclamation depends solely on H⁺ secretion, mediated by the apical Na⁺/H⁺ exchanger NHE₃ and the vacuolar proton pump. However, _NHE3 and the proton pump cannot account for all HCO₃^- reclamation. Here, we investigated the potential contribution of two variants of the electroneutral Na⁺/HCO₃^- cotransporter NBCn2, the amino termini of which start with the amino acids MCDL (MCDL-NBCn2) and MEIK (MEIK-NBCn2). Western blot analysis and immunocytochemistry revealed that MEIK-NBCn2 predominantly localizes at the basolateral membrane of medullary thick ascending limbs in the rat kidney, whereas MCDL-NBCn2 localizes at the apical membrane of proximal tubules. Notably, NH₄Cl-induced systemic metabolic acidosis or hypokalemic alkalosis downregulated the abundance of MCDL-NBCn2 and reciprocally upregulated NHE₃ Conversely, NaHCO₃-induced metabolic alkalosis upregulated MCDL-NBCn2 and reciprocally downregulated NHE₃ We propose that the apical membrane of the proximal tubules has two distinct strategies for HCO₃^- reclamation: the conventional indirect pathway, in which NHE₃ and the proton pump secrete H⁺ to titrate luminal HCO₃^-, and the novel direct pathway, in which NBCn2 removes HCO₃^- from the lumen. The reciprocal regulation of NBCn2 and NHE₃ under different physiologic conditions is consistent with our mathematical simulations, which suggest that HCO₃^- uptake and H⁺ secretion have reciprocal efficiencies for HCO₃^- reclamation versus titration of luminal buffers.

SUBMITTER: Guo YM 

PROVIDER: S-EPMC5533233 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature