%0 Journal Article
%T Renal antiporter ClC-5 regulates collagen I/IV through the β-catenin pathway and lysosomal degradation.
%A Durán M
%A Ariceta G
%A Semidey ME
%A Castells-Esteve C
%A Casal-Pardo A
%A Lu B
%A Meseguer A
%A Cantero-Recasens G
%J Life Sci Alliance
%V 7
%N 7
%D 2024 Jul
%M 38670633
%F 5.781
%R 10.26508/lsa.202302444
%X 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.