Dent’s disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding...Dent’s disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl-/H＋ antiporter chloride channel 5 （CLC-5）, which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H＋-ATPase （V-ATPase）. Initially identified as a member of the CLC family of Cl- channels, CLC-5 was presumed to provide Cl shunt into the endosomal lumen to dissipate H＋ accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl- channel but a 2Cl-/H＋ antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artifcial Cl- channel mutation E211A that developed defective endocytosis but normal endo-somal acidification. Conversely, a recent functional analysis of a newly identifed disease-causing Cl- channel mutation E211Q in a patient with typical Dent’s disease confrmed the functional coupling between V-ATPase and CLC-5 in endosomal acidifcation, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.展开更多
文摘Dent’s disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the CLCN5 gene coding for the electrogenic 2Cl-/H＋ antiporter chloride channel 5 （CLC-5）, which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H＋-ATPase （V-ATPase）. Initially identified as a member of the CLC family of Cl- channels, CLC-5 was presumed to provide Cl shunt into the endosomal lumen to dissipate H＋ accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl- channel but a 2Cl-/H＋ antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl- accumulation via CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artifcial Cl- channel mutation E211A that developed defective endocytosis but normal endo-somal acidification. Conversely, a recent functional analysis of a newly identifed disease-causing Cl- channel mutation E211Q in a patient with typical Dent’s disease confrmed the functional coupling between V-ATPase and CLC-5 in endosomal acidifcation, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.
