Caveolin‐1 deficiency induces a MEK‐ERK1/2‐Snail‐1‐dependent epithelial–mesenchymal transition and fibrosis during peritoneal dialysis

Abstract

Abstract 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‐ERK1/2‐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 MCs 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.

Keywords

• caveolin‐1
• epithelial–mesenchymal transition
• fibrosis
• MEK‐ERK1/2 pathway
• peritoneal dialysis