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

EMBO Molecular Medicine

Raffaele Strippoli²  Jesús Loureiro¹  Vanessa Moreno²  Ignacio Benedicto¹  María Luisa Pérez Lozano¹  Olga Barreiro²  Teijo Pellinen²  Susana Minguet²  Miguel Foronda²  Maria Teresa Osteso²  Enrique Calvo³  Jesús Vázquez³  Manuel López Cabrera¹ 

[1] Molecular Biology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain;Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;CIBERehd, Instituto de Salud Carlos III, Madrid, Spain

关键词: caveolin‐1;    epithelial–mesenchymal transition;    fibrosis;    MEK‐ERK1/2 pathway;    peritoneal dialysis;   

DOI  :  10.15252/emmm.201404127

来源: Wiley

【 摘 要 】

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.

• 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.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.