beta-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/beta-catenin signaling in mice.
beta-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/beta-catenin signaling in mice.
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beta-Arrestin-1 缺陷可通过阻断小鼠体内的 Wnt1/beta-catenin 信号传导来改善肾间质纤维化。
DOI：
10.1007/s00109-017-1606-5
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Yi Fan
中科院分区：
文献类型：
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作者：
Xu Huiyan;Li Quanxin;Liu Jiang;Zhu Jiaqing;Li Liang;Wang Ziying;Zhang Yan;Sun Yu;Sun Jinpeng;Wang Rong;Yi Fan
摘要尽管对肾纤维化发病机制的研究取得了很大进展，但目前临床上治疗或预防肾纤维化的方法仍不多。因此，明确参与肾纤维化发病机制的关键细胞和分子介质将为慢性肾脏病（CKD）患者的治疗提供新的治疗策略。β-Arrestin-1是β-arrestin家族的成员之一，它不仅是G蛋白偶联受体（GPCR）的负性接头蛋白，而且作为一种支架蛋白，不依赖于GPCR的激活而调节多种细胞功能。在这项研究中，我们首次发现β-arrestin-1在单侧输尿管梗阻性肾病小鼠的肾脏中以及在糖尿病肾病、多囊肾或尿肾病患者的人肾脏石蜡包埋切片中上调，这些患者通常会导致肾纤维化。在体内和体外研究中，小鼠中β-arrestin-1的缺乏通过调节炎症反应、肾成纤维细胞活化和上皮-间质转化（EMT）显著减轻肾纤维化。此外，我们发现在Wnt的主要亚型中，Wnt 1受β-arrestin-1的调控，并且Wnt 1的基因沉默抑制β-catenin的活化并抑制β-arrestin-1介导的肾纤维化。总之，我们的研究结果表明，β-arrestin-1是肾纤维化发展中信号转导途径的关键组分之一。关键信息β-Arrestin-1在UUO肾病小鼠肾脏中表达上调，β-Arrestin-1调节肾脏成纤维细胞活化和上皮-间质转化，β-Arrestin-1通过介导Wnt 1/β-catenin信号加重肾纤维化。
AbstractDespite substantial progress being made in understanding the mechanisms contributing to the pathogenesis of renal fibrosis, there are only a few therapies available to treat or prevent renal fibrosis in clinical use today. Therefore, identifying the key cellular and molecular mediators involved in the pathogenesis of renal fibrosis will provide new therapeutic strategy for treating patients with chronic kidney disease (CKD). β-Arrestin-1, a member of β-arrestin family, not only is a negative adaptor of G protein-coupled receptors (GPCRs), but also acts as a scaffold protein and regulates a diverse array of cellular functions independent of GPCR activation. In this study, we identified for the first time that β-arrestin-1 was upregulated in the kidney from mice with unilateral ureteral obstruction nephropathy as well as in the paraffin-embedded sections of human kidneys from the patients with diabetic nephropathy, polycystic kidney, or uronephrosis, which normally causes renal fibrosis. Deficiency of β-arrestin-1 in mice significantly alleviated renal fibrosis by the regulation of inflammatory responses, kidney fibroblast activation, and epithelial-mesenchymal transition (EMT) in both in vivo and in vitro studies. Furthermore, we found that among the major isoforms of Wnts, Wnt1 was regulated by β-arrestin-1 and gene silencing of Wnt1 inhibited the activation of β-catenin and suppressed β-arrestin-1-mediated renal fibrosis. Collectively, our results indicate that β-arrestin-1 is one of the critical components of signal transduction pathways in the development of renal fibrosis. Modulation of these pathways may be an innovative therapeutic strategy for treating patients with renal fibrosis.Key messagesβ-Arrestin-1 was upregulated in the kidney from mice with UUO nephropathy.β-Arrestin-1 regulated kidney fibroblast activation and epithelial-mesenchymal transition.β-Arrestin-1 exacerbated renal fibrosis via mediating Wnt1/β-catenin signaling.