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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.21.537823v1?rss=1 Authors: Duran, M., Ariceta, G., Semidey, M. E., Castells-Esteve, C., Lu, B., Meseguer, A., Cantero, G. Abstract: Mutations in the Cl-/H+ antiporter ClC-5 cause Dent 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. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC