Strippoli, RaffaeleLoureiro, JesusMoreno, VanessaBenedicto, IgnacioPerez Lozano, Maria LuisaBarreiro, OlgaPellinen, TeijoMinguet, SusanaForonda, MiguelOsteso, Maria TeresaCalvo, EnriqueVazquez, JesusLopez Cabrera, Manueldel Pozo, Miguel Angel2017-12-012017-12-012015EMBO Mol Med. 2015; 7(1):102-231757-4676http://hdl.handle.net/20.500.12105/5527Peritoneal 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-beta 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Caveolin-1Epithelial-mesenchymal transitionFibrosisMEK-ERK1/2 pathwayPeritoneal dialysisENDOTHELIAL GROWTH-FACTORE-CADHERIN EXPRESSIONMAP KINASE PATHWAYNF-KAPPA-BMESOTHELIAL CELLSTGF-BETATRANSCRIPTIONAL ACTIVITYQUANTITATIVE PROTEOMICSSCAFFOLDING DOMAINPULMONARY DEFECTSAtribución 4.0 Internacional255503957102-1231757-4684EMBO Molecular Medicineopen access