Satoh Nobuhiko, Suzuki Masashi, Nakamura Motonobu, Suzuki Atsushi, Horita Shoko, Seki George, Moriya Kyoji
Nobuhiko Satoh, Masashi Suzuki, Motonobu Nakamura, Atsushi Suzuki, Shoko Horita, Department of Internal Medicine, Faculty of Medicine, the University of Tokyo Hospital, Tokyo 113-8655, Japan.
World J Nephrol. 2017 Jan 6;6(1):14-20. doi: 10.5527/wjn.v6.i1.14.
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 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 CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl channel mutation E211Q 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.
丹特病是一种X连锁肾小管病，其特征为低分子量蛋白尿、高钙尿症和进行性肾衰竭。该病的病因与编码电中性2Cl/H逆向转运体氯离子通道5（CLC-5）的基因突变有关，该通道与液泡型H-ATP酶（V-ATP酶）一起表达于肾近端小管的顶端内体中。CLC-5最初被鉴定为Cl通道的CLC家族成员，推测其可将Cl转运至内体腔以消散V-ATP酶积累的H，从而促进内体的有效酸化。然而，最近的研究结果表明CLC-5实际上并非Cl通道而是2Cl/H逆向转运体，这对经典的转运模型提出了挑战，引发了关于其生理作用的新一轮激烈争论。Cl积累 CLC-5预计在内吞作用中起关键作用，如在携带人工Cl通道突变E211A的小鼠中所示，这些小鼠出现了内吞缺陷但内体酸化正常。相反，最近对一名典型丹特病患者新发现的致病Cl通道突变E211Q进行的功能分析证实了V-ATP酶与CLC-5在内体酸化中的功能偶联，支持了经典的转运模型。在这篇社论中，我们将阐述目前对CLC-5生理作用的认识，特别关注V-ATP酶与CLC-5的功能偶联。
