Tubulointerstitial fibrosis plays an important role in end‐stage renal failure, and there are only limited therapeutic options available to preserve organ function. In the present study, we identified that nodakenin, a coumarin isolated from the roots of Angelicae gigas, functions effectively against unilateral ureteral obstruction (UUO)‐induced fibrosis via down‐regulating Snail1 expression. We established UUO‐induced renal fibrosis in mice and then administered with nodakenin orally ata a dose of 1 and 10 mg/kg. The in‐vivo results indicated that nodakenin protected obstructive nephropathy through its anti‐inflammatory and anti‐fibrotic properties. Nodakenin prevented the infiltration of inflammatory cells, alleviated the levels of pro‐inflammatory cytokines, reduced the polarization of macrophages and down‐regulating the aberrant deposition of extracellular matrix at the site of injury. Of note, nodakenin dramatically impeded Smad3, NF‐κB p65 phosphorylation and Snail1 expression. In line with in vivo studies, nodakenin suppressed the expression of Snail1, Smad3 phosphorylation and fibrogenesis in TGF‐β1‐treated renal epithelial cells in‐vitro. Furthermore, we found that the effect of nodaknin against fibrosis was reversed in Snail1 overexpressing cells, whereas nodakenin could not further reduce expression of fibrogenesis in Snail1 silenced cells, suggesting that nodaknein may function through a Snail1‐dependent manner. Collectively, this study reveal a critical role of nodakenin in the cure of renal fibrosis.

中文翻译：

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Nodakenin 通过减弱 Snail1 诱导的纤维化来缓解阻塞性肾病。

肾小管间质纤维化在终末期肾功能衰竭中起着重要作用，可用于保护器官功能的治疗选择有限。在本研究中，我们发现 nodakenin 是一种从当归根中分离的香豆素，通过下调 Snail1 表达有效对抗单侧输尿管梗阻 (UUO) 诱导的纤维化。我们在小鼠中建立了 UUO 诱导的肾纤维化，然后以 1 和 10 mg/kg 的剂量口服给予 nodakenin。在体内结果表明，nodakenin 通过其抗炎和抗纤维化特性保护梗阻性肾病。Nodakenin 阻止炎症细胞的浸润，降低促炎细胞因子的水平，减少巨噬细胞的极化并下调损伤部位细胞外基质的异常沉积。值得注意的是，nodakenin 显着阻碍了 Smad3、NF-κB p65 磷酸化和 Snail1 表达。与体内研究一致，nodakenin在体外抑制 TGF-β1 处理的肾上皮细胞中Snail1、Smad3 磷酸化和纤维化的表达. 此外，我们发现 nodaknein 对纤维化的作用在 Snail1 过表达细胞中被逆转，而 nodaknein 不能进一步降低 Snail1 沉默细胞中纤维化的表达，表明 nodaknein 可能通过 Snail1 依赖性方式发挥作用。总的来说，这项研究揭示了 nodakenin 在治疗肾纤维化中的关键作用。