Caveolin‐1 deficiency induces a MEK ‐ ERK 1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Peritoneal dialysis ( PD ) is a form of renal replacement therapy whose repeated use can alter dialytic function through induction of epithelial–mesenchymal transition ( EMT ) and fibrosis, eventually leading to PD discontinuation. The peritoneum from Cav1 −/− mice showed increased EMT , thickness, and fibrosis. Exposure of Cav1 −/− mice to PD fluids further increased peritoneal membrane thickness, altered permeability, and increased the number of FSP ‐1/cytokeratin‐positive cells invading the sub‐mesothelial stroma. High‐throughput quantitative proteomics revealed increased abundance of collagens, FN , and laminin, as well as proteins related to TGF ‐β activity in matrices derived from Cav1 −/− cells. Lack of Cav1 was associated with hyperactivation of a MEK ‐ ERK 1/2‐Snail‐1 pathway that regulated the Smad2‐3/Smad1‐5‐8 balance. Pharmacological blockade of MEK rescued E‐cadherin and ZO ‐1 inter‐cellular junction localization, reduced fibrosis, and restored peritoneal function in Cav1 −/− mice. Moreover, treatment of human PD ‐patient‐derived MC s with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induced re‐acquisition of epithelial features. This study demonstrates a pivotal role of Cav1 in the balance of epithelial versus mesenchymal state and suggests targets for the prevention of fibrosis during PD .