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Role of endothelin‐1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis
Author(s) -
Motegi Seiichiro,
Okada Etsuko,
Uchiyama Akihiko,
Yamada Kazuya,
Ogino Sachiko,
Yokoyama Yoko,
Takeuchi Yuko,
Monma Fumiko,
Suzuki Tamio,
Ishikawa Osamu
Publication year - 2014
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12500
Subject(s) - nephrogenic systemic fibrosis , endothelin receptor , fibrosis , calcification , medicine , endothelin 1 , endothelins , endocrinology , receptor , kidney disease
Nephrogenic systemic fibrosis ( NSF ) is characterized by systemic fibrosis and abnormal calcification in patients with severe renal dysfunction. It is considered that gadolinium (Gd)‐containing contrast agents used for magnetic resonance imaging trigger the development of NSF . However, the causative role of Gd and the mechanism of Gd‐induced fibrosis and calcification in NSF are unknown. Recently, it has been known that endothelin‐1 ( ET ‐1)/ ET receptor ( ETR ) signalling regulates fibrosis and calcification. The objective was to elucidate the role of ET ‐1/ ETR signalling in Gd‐induced fibrosis and calcification in NSF . First, we demonstrated that Gd enhanced proliferation and calcification of human adipose tissue‐derived mesenchymal stem cells ( hMSC ) in vitro . Next, we examined the expression of ET ‐1 and ETR ‐A in hMSC using proliferation or calcification assay. ET ‐1 and ETR ‐A expression in hMSC treated with Gd were elevated. ET ‐1/ ETR signalling inhibitor, bosentan, inhibited Gd‐induced proliferation and calcification of hMSC . In addition, bosentan inhibited Gd‐induced phosphorylation of ERK and Akt in hMSC . Plasma ET ‐1 levels of the patients were significantly higher than these of normal individuals and systemic sclerosis patients. In immunofluorescence staining, the expression of ETR ‐A in fibroblasts in dermal fibrosis lesion of NSF was increased. We conclude that Gd induces proliferation and calcification of hMSC via enhancement of ET ‐1/ ETR signalling. Our results contribute to understand the pathogenesis of NSF .