Caveolin-1 deficiency induces a MEK-ERK1/2-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-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. Caveolin-1 (Cav1) limits the occurrence of EMT and fibrosis during peritoneal dialysis. Absence of Cav1 is associated to hyper-activation of the MEK-ERK-Snail-1 axis, which affects the SMAD2-3/SMAD1-5-8 balance. MEK inhibition prevents EMT, fibrosis, and altered peritoneal membrane function in the peritoneum of Cav1^-/- mice undergoing peritoneal dialysis. Treatment of human peritoneal dialysis patient-derived mesothelial cells with drugs increasing Cav1 levels, as well as ectopic Cav1 expression, induce re-acquisition of epithelial features. 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.