title: ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.
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 alpha-intercalated cells. In transfected cells, ClC-5 colocalizes with endocytosed alpha2-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.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg (ZMNH), Universität Hamburg, Martinistrasse 85, D-20246 Hamburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Günther
authors.forename: A
authors.initials: A
authors.lastname: Lüchow
authors.forename: F
authors.initials: F
authors.lastname: Cluzeaud
authors.forename: A
authors.initials: A
authors.lastname: Vandewalle
authors.forename: T J
authors.initials: TJ
authors.lastname: Jentsch
mesh_terms: D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D004705:Endocytosis; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology*; D009154:Mutation; D009397:Nephrocalcinosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017494:Proton Pumps / Q000378:metabolism*; D013577:Syndrome; D014162:Transfection
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D017494:Proton Pumps