Endosomal Chloride-Proton Exchange Rather Than Chloride Conductance Is Crucial for Renal Endocytosis

Loss of the endosomal anion transport protein ClC-5 impairs renal endocytosis and underlies human Dent’s disease. ClC-5 is thought to promote endocytosis by facilitating endosomal acidification through the neutralization of proton pump currents. However, ClC-5 is a 2 chloride (Cl –)/proton ( /H + ) exchanger rather than a Cl – channel. We generated mice that carry the uncoupling E211A (unc) mutation that converts ClC-5 into a pure Cl – conductor. Adenosine triphosphate (ATP)–dependent acidification of renal endosomes was reduced in mice in which ClC-5 was knocked out, but normal in Clcn5 unc mice. However, their proximal tubular endocytosis was also impaired. Thus, endosomal chloride concentration, which is raised by ClC-5 in exchange for protons accumulated by the H + -ATPase, may play a role in endocytosis.