Basic ResearchA Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated FibrosisBusnadiego, Oscar*; Loureiro-Álvarez, Jesús*,†; Sandoval, Pilar*; Lagares, David*; Dotor, Javier‡; Pérez-Lozano, María Luisa*; López-Armada, María J.†; Lamas, Santiago*; López-Cabrera, Manuel*; Rodríguez-Pascual, Fernando* Author Information *Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; †Laboratorio de Envejecimiento e Inflamación, Instituto de Investigación Biomédica, A Coruña, A Coruña, Spain; and ‡Digna Biotech, Madrid, Spain Correspondence: Dr. Fernando Rodríguez-Pascual, Centro de Biología Molecular “Severo Ochoa,” Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), Nicolás Cabrera, 1 E28049, Madrid, Spain. Email: [email protected] Received July 29, 2013 Accepted April 30, 2014 Journal of the American Society of Nephrology 26(1):p 173-182, January 2015. | DOI: 10.1681/ASN.2013070799 Buy Metrics Abstract In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-β1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-β1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-β1–blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-β1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-β1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD-associated dysfunction. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.