Na/HCO Cotransporter NBCn2 Mediates HCO Reclamation in the Apical Membrane of Renal Proximal Tubules.

The kidney maintains systemic acid-base balance by reclaiming from the renal tubule lumen virtually all HCO 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 HCO reclamation depends solely on H secretion, mediated by the apical Na/H exchanger NHE and the vacuolar proton pump. However, and the proton pump cannot account for all HCO reclamation. Here, we investigated the potential contribution of two variants of the electroneutral Na/HCO 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, NHCl-induced systemic metabolic acidosis or hypokalemic alkalosis downregulated the abundance of MCDL-NBCn2 and reciprocally upregulated NHE Conversely, NaHCO-induced metabolic alkalosis upregulated MCDL-NBCn2 and reciprocally downregulated NHE We propose that the apical membrane of the proximal tubules has two distinct strategies for HCO reclamation: the conventional indirect pathway, in which NHE and the proton pump secrete H to titrate luminal HCO, and the novel direct pathway, in which NBCn2 removes HCO from the lumen. The reciprocal regulation of NBCn2 and NHE under different physiologic conditions is consistent with our mathematical simulations, which suggest that HCO uptake and H secretion have reciprocal efficiencies for HCO reclamation versus titration of luminal buffers.