Functional coupling of V-ATPase and CLC-5
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 express...
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Veröffentlicht in: | World journal of nephrology 2017-01, Vol.6 (1), p.14-20 |
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Sprache: | eng |
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Zusammenfassung: | 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 artificial Cl- channel mutation E211 A that developed defective endocytosis but normal endosomal acidification. Conversely,a recent functional analysis of a newly identified disease-causing Cl~- channel mutation E211 Q in a patient with typical Dent’s disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification,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. |
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ISSN: | 2220-6124 2220-6124 |
DOI: | 10.5527/wjn.v6.i1.14 |