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- Title
Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis.
- Authors
Motegi, Sei‐ichiro; Okada, Etsuko; Uchiyama, Akihiko; Yamada, Kazuya; Ogino, Sachiko; Yokoyama, Yoko; Takeuchi, Yuko; Monma, Fumiko; Suzuki, Tamio; Ishikawa, Osamu
- Abstract
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 Gdinduced 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.
- Subjects
ENDOTHELIN receptors; CELLULAR signal transduction; FIBROSIS; CALCIFICATION; KIDNEY diseases; MAGNETIC resonance imaging; PATIENTS; DIAGNOSIS
- Publication
Experimental Dermatology, 2014, Vol 23, Issue 9, p664
- ISSN
0906-6705
- Publication type
Article
- DOI
10.1111/exd.12500