title: Caveolin-1 deficiency induces a MEK-ERK1/2-Snail-1-dependent epithelial-mesenchymal transition and fibrosis during peritoneal dialysis.
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.
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy raffaele.strippoli@uniroma1.it madelpozo@cnic.es.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Strippoli
authors.affiliation: Molecular Biology Unit, Hospital Universitario de la Princesa Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Loureiro
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Moreno
authors.affiliation: Molecular Biology Unit, Hospital Universitario de la Princesa Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Benedicto
authors.affiliation: Molecular Biology Unit, Hospital Universitario de la Princesa Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Pérez Lozano
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Teijo
authors.initials: T
authors.lastname: Pellinen
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Foronda
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Osteso
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Calvo
authors.affiliation: CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Molecular Biology Unit, Hospital Universitario de la Princesa Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: López Cabrera
authors.affiliation: Department of Vascular biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain raffaele.strippoli@uniroma1.it madelpozo@cnic.es.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: del Pozo
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051242:Caveolin 1; C000604407:SNAI1 protein, human; D051785:Smad Proteins; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: MEK‐ERK1/2 pathway; caveolin‐1; epithelial–mesenchymal transition; fibrosis; peritoneal dialysis