Na+/HCO3 – Cotransporter NBCn2 Mediates HCO3 − 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 3 − 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 3 − reclamation depends solely on H + secretion, mediated by the apical Na + /H + exchanger NHE 3 and the vacuolar proton pump. However, NHE3 and the proton pump cannot account for all HCO 3 − reclamation. Here, we investigated the potential contribution of two variants of the electroneutral Na + /HCO 3 – 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, NH 4 Cl-induced systemic metabolic acidosis or hypokalemic alkalosis downregulated the abundance of MCDL-NBCn2 and reciprocally upregulated NHE 3 . Conversely, NaHCO 3 -induced metabolic alkalosis upregulated MCDL-NBCn2 and reciprocally downregulated NHE 3 . We propose that the apical membrane of the proximal tubules has two distinct strategies for HCO 3 − reclamation: the conventional indirect pathway, in which NHE 3 and the proton pump secrete H + to titrate luminal HCO 3 − , and the novel direct pathway, in which NBCn2 removes HCO 3 − from the lumen. The reciprocal regulation of NBCn2 and NHE 3 under different physiologic conditions is consistent with our mathematical simulations, which suggest that HCO 3 − uptake and H + secretion have reciprocal efficiencies for HCO 3 − reclamation versus titration of luminal buffers.