title: Role of endothelin-1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis.
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 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.
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Sei-Ichiro
authors.initials: S
authors.lastname: Motegi
authors.forename: Etsuko
authors.initials: E
authors.lastname: Okada
authors.forename: Akihiko
authors.initials: A
authors.lastname: Uchiyama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamada
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ogino
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Monma
authors.forename: Tamio
authors.initials: T
authors.lastname: Suzuki
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
mesh_terms: D000293:Adolescent; D000077300:Bosentan; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003287:Contrast Media / Q000009:adverse effects; D065128:Endothelin Receptor Antagonists / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D005682:Gadolinium / Q000009:adverse effects; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000009:adverse effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D054989:Nephrogenic Fibrosing Dermopathy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D003287:Contrast Media; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D005682:Gadolinium; C038958:gadolinium chloride; D000077300:Bosentan
keywords: calcification; endothelin-1; fibrosis; mesenchymal stem cells; nephrogenic systemic fibrosis