ClC-5, the chloride channel mutated in Dent’s disease, colocalizes with the proton pump in endocytotically active kidney cells

TLDR

Dent’s disease arises from loss‑of‑function mutations in the ClC‑5 chloride channel, causing low‑molecular‑weight proteinuria, hypercalciuria, and kidney stones. The authors aim to determine whether ClC‑5 is essential for proximal tubular endocytosis. They propose that ClC‑5 provides an electrical shunt that enables efficient acidification of endocytic vesicles. ClC‑5 is expressed in proximal tubule and intercalated cells, colocalizes with the H⁺‑ATPase and internalized proteins, and its presence in enlarged early endosomes is enhanced by a GTPase‑deficient Rab5 mutant.

Abstract

Loss-of-function mutations of the ClC-5 chloride channel lead to Dent’s disease, a syndrome characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. We show that ClC-5 is expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression is highest below the brush border in a region densely packed with endocytotic vesicles, where ClC-5 colocalizes with the H + -ATPase and with internalized proteins early after uptake. In intercalated cells of the collecting duct it again localizes to apical intracellular vesicles and colocalizes with the proton pump in α-intercalated cells. In transfected cells, ClC-5 colocalizes with endocytosed α 2 -macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant leads to enlarged early endosomes that stain for ClC-5. We suggest that ClC-5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent’s disease.