FoxM1 inhibition ameliorates renal interstitial fibrosis by decreasing extracellular matrix and epithelial-mesenchymal transition
FoxM1 inhibition ameliorates renal interstitial fibrosis by decreasing extracellular matrix and epithelial-mesenchymal transition
复制标题
DOI：
10.1016/j.jphs.2020.05.007
复制
发表时间：
2020-08-01
影响因子：
3.5
通讯作者：
He, Ting
中科院分区：
文献类型：
--
作者：
Wang, Yanhui;Zhou, Qiaoling;He, Ting
FoxM 1是一种转录调节因子，参与肿瘤的发生、肺纤维化和心脏纤维化。然而，其在肾间质纤维化（RIF）中的作用尚未阐明。我们建立了TGF-β 1刺激的人近端肾小管上皮细胞（HK-2）体外模型和单侧输尿管梗阻（UUO）诱导的大鼠RIF体内模型。FoxM 1抑制通过siRNA干扰在体外和通过注射硫链丝菌素到UUO诱导的RIF大鼠体内实现。通过苏木精和伊红（H&E）染色的组织学评估来确定肾损伤和纤维化的程度。采用免疫组织化学、蛋白质印迹和qPCR测定FoxM 1、胶原蛋白I、E-钙粘蛋白、α-SMA和Snail 1的表达水平。我们的结果表明，FoxM 1抑制可以改善RIF，减少胶原I的沉积。H&E染色显示，硫链丝菌素治疗UUO大鼠后，肾结构损伤、炎性细胞浸润和ECM沉积显著减弱。此外，FoxM 1下调显著抑制上皮-间充质转化，如α-SMA和Snail 1的蛋白和mRNA表达水平降低以及E-cadherin的蛋白和mRNA表达水平显著增加所证明的。总的来说，这些结果表明，FoxM 1抑制可能是治疗RIF的一种新的治疗策略。(C)2020年，任作家。Elsevier B. V.代表日本药理学会制作和主办。
FoxM1 is a transcriptional regulator involved in tumor development, pulmonary fibrosis, and cardiac fibrosis. However, its role in renal interstitial fibrosis (RIF) has yet to be elucidated. We established a TGF-beta 1-stimulated human proximal tubular epithelial cell (HK-2) model in vitro and a unilateral ureteral obstruction (UUO)-induced rat RIF model in vivo. FoxM1 inhibition was achieved by siRNA interference in vitro and by injecting thiostrepton into UUO-induced RIF rats in vivo. The degree of renal damage and fibrosis were determined by histological assessment via hematoxylin and eosin (H&E) staining. Immunohistochemistry, western blots, and qPCR were used to determine the expression levels of FoxM1, Collagen I, E-cadherin, alpha-SMA, and Snail1. Our results showed that FoxM1 inhibition could ameliorate RIF and reduce the deposition of Collagen I. H&E staining revealed that renal structural damage, inflammatory cell infiltration, and ECM deposition were significantly attenuated by thiostrepton treatment in the UUO rats. Furthermore, FoxM1 downregulation significantly suppressed epithelial-to-mesenchymal transition, as evidenced by decreased protein and mRNA expression levels of alpha-SMA and Snail1 and a significant increase in protein and mRNA expression levels of E-cadherin. Collectively, these results suggested that FoxM1 inhibition could be a novel therapeutic strategy for the treatment of RIF. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.