title: A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis.
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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Oscar
authors.initials: O
authors.lastname: Busnadiego
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Loureiro-Álvarez
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Pilar
authors.initials: P
authors.lastname: Sandoval
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: Digna Biotech, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Pérez-Lozano
authors.affiliation: Laboratorio de Envejecimiento e Inflamación, Instituto de Investigación Biomédica, A Coruña, A Coruña, Spain; and.
authors.forename: María J
authors.initials: MJ
authors.lastname: López-Armada
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Santiago
authors.initials: S
authors.lastname: Lamas
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cabrera
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain; frodriguez@cbm.csic.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez-Pascual
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000473:pathology*; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D053773:Transforming Growth Factor beta1
keywords: TGF-β1; endothelin-1; fibrosis; peritoneal dialysis; ultrafiltration