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

Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO₂) and water into bicarbonate (HCO₃^-) 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 HCO₃^- in specific nephron segments. Among these transporters are the Na⁺-coupled HCO₃^- transporters (NCBTs) and the Cl^--HCO₃^- exchangers (AEs)-members of the "solute-linked carrier" 4 (SLC4) family. All of these transporters have traditionally been regarded as "HCO₃^-" transporters. However, recently our group has demonstrated that two of the NCBTs carry CO₃^2- rather than HCO₃^- and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and "HCO₃^-" transporters of the SLC4 family in renal acid-base physiology and discuss how our recent findings impact renal acid secretion, including HCO₃^- reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO₂, HCO₃^-, and H⁺) and thus ensuring their efficient transport across cell membranes. In the case of CO₃^2- 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.