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

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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.

Synopsis

Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin-1 as an important regulator of these events.

Peritoneal dialysis (PD) has major advantages vs. hemodialysis but leads to inflammation and injury to the PM. This study identifies MEK/ERK1/2 signaling as playing a central role in EMT and fibrosis occurring during PD, and caveolin-1 as an important regulator of these events.

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