Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO(2)) and water into bicarbonate (HCO(3)(−)) and protons (H(+)), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid–base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO(3)(−) in specific nephron segments. Among these transporters are the Na(+)-coupled HCO(3)(−) transporters (NCBTs) and the Cl(−)-HCO(3)(−) exchangers (AEs)—members of the “solute-linked carrier” 4 (SLC4) family. All of these transporters have traditionally been regarded as “HCO(3)(−)“ transporters. However, recently our group has demonstrated that two of the NCBTs carry CO(3)(2−) rather than HCO(3)(−) and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and “HCO(3)(−)” transporters of the SLC4 family in renal acid–base physiology and discuss how our recent findings impact renal acid secretion, including HCO(3)(−) reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO(2), HCO(3)(−), and H(+)) and thus ensuring their efficient transport across cell membranes. In the case of CO(3)(2−) transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane.