Renal Cl-/H+ antiporter ClC-5 regulates collagen production and release in Dent Disease models

Mutations in the Cl-/H+ antiporter ClC-5 cause Dents Disease 1 (DD1), a rare primary tubulopathy that eventually progresses to renal failure. In fact, even with normal kidney function, DD1 patients present renal tubulointerstitial fibrosis. However, the link between ClC-5 loss-of-function and renal fibrosis remains unclear. Here, we have shown that DD1 mice models lacking ClC-5 present higher renal collagen deposition and fibrosis. Accordingly, deletion of ClC-5 in human renal proximal tubule epithelial cells (CLCN5 KD) recapitulates this effect. We have demonstrated that CLCN5 KD causes an increase of collagen I (Col I) and IV (Col IV) intracellular levels by promoting their transcription through {beta}-catenin pathway and impairing their lysosomal-mediated degradation. In addition, CLCN5 KD cells release more Col I and IV at the extracellular space that form fibres with altered properties and resistance to removal compared to control cells. 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. SIGNIFICANCE STATEMENTRenal fibrosis is a common pathologic process occurring as consequence of chronic kidney injury and leading to renal dysfunction. Dents Disease is a rare renal pathology that progresses to chronic kidney disease and tubulointerstitial fibrosis. Interestingly, it is caused by mutations in a single gene called CLCN5, therefore it can help understanding the cellular mechanisms of renal fibrosis. Using cellular and mice models of the disease, we describe a mechanism linking CLCN5 function, cell differentiation and regulation of collagen levels, major component of extracellular matrix and important player for renal fibrosis development. In conclusion, our results provide a link between CLCN5 and altered collagen deposition, which could be relevant for other renal Fanconi syndrome related diseases also progressing to fibrosis.