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Dent’s disease is a rare disorder of the proximal tubule caused by inactivating mutations in the endosomal chloride transporter ClC-5. The disease is characterized by defective endocytosis and manifestations of proximal tubule dysfunction (renal Fanconi syndrome) [1–3]. The primary defect in proximal tubule endocytosis has been attributed to an impaired vesicular acidification caused by the loss of endosomal Cl conductance mediated by ClC-5 (chloride shunt hypothesis) [4,5]. However, recent electrophysiological studies have shown that ClC-5 is a 2Cl/H exchanger rather than a Cl channel [6,7]. In order to test the relevance of this exchange activity for Dent’s disease, Novarino, Jentsch and colleagues [8] engineered a knockin (KI) mouse harbouring a point mutation in a critical glutamate residue which converts the exchanger into an uncoupled Cl channel that should facilitate endosomal acidification. They then compared these KI mice with the conventional knock-out (KO) mice that faithfully recapitulate the phenotype of Dent’s disease. As expected, acidification of the renal endosomes from WT and KI mice was normal, but severely impaired in KO mice. However, despite normal endosomal acidification, KI mice showed the same renal phenotype as KO mice and patients with Dent’s disease, including low-molecular-weight proteinuria, hyperphosphaturia and hypercalciuria. Furthermore, both the KI and KO mouse showed impaired proximal tubule endocytosis and a similar trafficking defect. Thus, proximal tubule dysfunction in Dent’s disease may occur despite normal acidification of renal endosomes. These findings, which exclude the chloride shunt hypothesis, suggest a role for a reduced endosomal chloride accumulation in Dent’s disease and point to the importance of chloride concentration for organelle physiology. Review of the field

Dent's disease: chloride-proton exchange controls proximal tubule endocytosis