A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β(1) pathways.
A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β(1) pathways.
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DOI：
10.1038/s41598-017-01702-7
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发表时间：
2017-05-15
影响因子：
4.6
通讯作者：
Abe T
中科院分区：
文献类型：
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作者：
Shima H;Sasaki K;Suzuki T;Mukawa C;Obara T;Oba Y;Matsuo A;Kobayashi T;Mishima E;Watanabe S;Akiyama Y;Kikuchi K;Matsuhashi T;Oikawa Y;Nanto F;Akiyama Y;Ho HJ;Suzuki C;Saigusa D;Masamune A;Tomioka Y;Masaki T;Ito S;Hayashi KI;Abe T
肾纤维化与慢性炎症密切相关，并受到表观遗传调控。由于转化生长因子-β1 (TGF-β1) 和肿瘤坏死因子-α (TNF-α) 的信号传导在肾纤维化的进展中发挥关键作用，因此需要双重阻断 TGF-β1 和 TNF-α 作为其治疗方法。在这里，我们在吲哚衍生物化合物库中筛选了具有抗TNF-α活性的小分子。 41 种吲哚衍生物中有 11 种抑制 TNF-α 作用。其中，线粒体酸35（MA-35）、5-（3,5-二甲氧基苄氧基）-3-吲哚乙酸显示出有效的效果。抗 TNF-α 活性是通过抑制 IκB 激酶磷酸化介导的，从而减轻了 LPS/GalIN 诱导的小鼠肝脏炎症。此外，MA-35 同时通过抑制 Smad3 磷酸化表现出抗 TGF-β1 作用，导致 TGF-β1 诱导的纤维化基因表达下调。在单侧输尿管阻塞的小鼠肾脏（肾纤维化模型）中，MA-35 通过下调炎症细胞因子和纤维化基因表达来减轻肾脏炎症和纤维化。此外，MA-35 抑制 TGF-β1 诱导的纤维化基因启动子的 H3K4me1 组蛋白修饰，导致纤维化基因表达减少。 MA-35影响参与纤维化的多个信号通路，并可能恢复表观遗传修饰；因此，它可能是一种新型的纤维化治疗药物。
Renal fibrosis is closely related to chronic inflammation and is under the control of epigenetic regulations. Because the signaling of transforming growth factor-β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) play key roles in progression of renal fibrosis, dual blockade of TGF-β1 and TNF-α is desired as its therapeutic approach. Here we screened small molecules showing anti-TNF-α activity in the compound library of indole derivatives. 11 out of 41 indole derivatives inhibited the TNF-α effect. Among them, Mitochonic Acid 35 (MA-35), 5-(3, 5-dimethoxybenzyloxy)-3-indoleacetic acid, showed the potent effect. The anti-TNF-α activity was mediated by inhibiting IκB kinase phosphorylation, which attenuated the LPS/GaIN-induced hepatic inflammation in the mice. Additionally, MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad3 phosphorylation, resulting in the downregulation of TGF-β1-induced fibrotic gene expression. In unilateral ureter obstructed mouse kidney, which is a renal fibrosis model, MA-35 attenuated renal inflammation and fibrosis with the downregulation of inflammatory cytokines and fibrotic gene expressions. Furthermore, MA-35 inhibited TGF-β1-induced H3K4me1 histone modification of the fibrotic gene promoter, leading to a decrease in the fibrotic gene expression. MA-35 affects multiple signaling pathways involved in the fibrosis and may recover epigenetic modification; therefore, it could possibly be a novel therapeutic drug for fibrosis.