Role of endothelin‐1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis
Role of endothelin‐1/endothelin receptor signaling in fibrosis and calcification in nephrogenic systemic fibrosis
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DOI：
10.1111/exd.12500
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发表时间：
2014-09
影响因子：
3.6
通讯作者：
S. Motegi;E. Okada;A. Uchiyama;Kazuya Yamada;S. Ogino;Y. Yokoyama;Y. Takeuchi;F. Monma;Tamio Suzuki;O. Ishikawa
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文献类型：
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作者：
S. Motegi;E. Okada;A. Uchiyama;Kazuya Yamada;S. Ogino;Y. Yokoyama;Y. Takeuchi;F. Monma;Tamio Suzuki;O. Ishikawa
肾源性全身性纤维化(NSF)是以严重肾功能不全患者的全身性纤维化和异常钙化为特征。核磁共振成像中使用的含Gd造影剂被认为是NSF的诱因。然而，Gd在NSF中的致病作用和Gd诱导的纤维化和钙化机制尚不清楚。近年来，已知内皮素-1(ET-1)/ET受体(ETR)信号通路调节纤维化和钙化。目的是阐明ET-1/ETR信号通路在Gd诱导的NSF纤维化和钙化中的作用。首先，我们证明了Gd促进了人脂肪组织来源的间充质干细胞(HMSC)的体外增殖和钙化。接下来，我们通过增殖或钙化实验检测了ET-1和ETR-A在hMSC中的表达。Gd可上调HMSC ET-1和ETR-A的表达。ET-1/ETR信号转导抑制剂波生坦可抑制Gd诱导的hMSC增殖和钙化。此外，波生坦还可抑制Gd诱导的hMSC中ERK和Akt的磷酸化。患者血浆ET-1水平明显高于正常人和系统性硬化症患者。免疫荧光染色显示，NSF真皮纤维化病变成纤维细胞ETR-A表达增强。结论：Gd通过增强ET-1/ETR信号通路诱导HMSC增殖和钙化。我们的结果有助于了解NSF的发病机制。
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.