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Title

A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis

AuthorsBusnadiego, Óscar ; Loureiro, Jesús ; Sandoval, Pilar ; Lagares, David ; Dotor, Javier; Pérez-Lozano, María Luisa ; López-Armada, María J.; Lamas Peláez, Santiago ; López Cabrera, Manuel ; Rodríguez-Pascual, Fernando
Issue Date2015
PublisherLippincott Williams & Wilkins
CitationJournal of the American Society of Nephrology : JASN 26: 173- 182 (2015)
AbstractCopyright © 2015 by the American Society of Nephrology. 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 myo fibroblasts, 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 humanmesothelial 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.
URIhttp://hdl.handle.net/10261/133213
DOIhttp://dx.doi.org/10.1681/ASN.2013070799
ISSN1533-3450
Identifiersdoi: 10.1681/ASN.2013070799
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