PDF(Pubmed)
Abstract：
Mutations in Cl-/H+ antiporter ClC-5 cause Dent\'s disease type 1 (DD1), a rare tubulopathy that progresses to renal fibrosis and kidney failure. Here, we have used DD1 human cellular models and renal tissue from DD1 mice to unravel the role of ClC-5 in renal fibrosis. Our results in cell systems have shown that ClC-5 deletion causes an increase in collagen I (Col I) and IV (Col IV) intracellular levels by promoting their transcription through the β-catenin pathway and impairing their lysosomal-mediated degradation. Increased production of Col I/IV in ClC-5-depleted cells ends up in higher release to the extracellular medium, which may lead to renal fibrosis. Furthermore, our data have revealed that 3-mo-old mice lacking ClC-5 (Clcn5 +/- and Clcn5 -/- ) present higher renal collagen deposition and fibrosis than WT mice. Altogether, we describe a new regulatory mechanism for collagens\' production and release by ClC-5, which is altered in DD1 and provides a better understanding of disease progression to renal fibrosis.
摘要：
Cl-/H+反转运蛋白ClC-5的突变导致Dent病1型(DD1),一种罕见的肾小管病，进展为肾纤维化和肾衰竭。这里,我们使用DD1人细胞模型和DD1小鼠的肾组织来揭示ClC-5在肾纤维化中的作用.我们在细胞系统中的结果表明，ClC-5缺失通过β-连环蛋白途径促进其转录并损害其溶酶体介导的降解，从而导致胶原蛋白I（ColI）和IV（ColIV）细胞内水平的增加。ClC-5耗尽细胞中ColI/IV产量的增加最终导致向细胞外培养基的更高释放，这可能导致肾脏纤维化。此外，我们的数据显示,缺乏ClC-5(Clcn5+/-和Clcn5-/-)的3月龄小鼠的肾脏胶原沉积和纤维化程度高于WT小鼠.总之,我们描述了ClC-5产生和释放胶原蛋白的新调节机制,该机制在DD1中发生了改变,并提供了对疾病进展为肾纤维化的更好理解.
