A Novel Inhibitor of Homodimerization Targeting MyD88 Ameliorates Renal Interstitial Fibrosis by Counteracting TGF-β1-Induced EMT in Vivo and in Vitro
A Novel Inhibitor of Homodimerization Targeting MyD88 Ameliorates Renal Interstitial Fibrosis by Counteracting TGF-β1-Induced EMT in Vivo and in Vitro
复制标题
一种针对 MyD88 的新型同二聚化抑制剂通过对抗体内和体外 TGF-β1 诱导的 EMT 来改善肾间质纤维化
DOI：
10.1159/000494745
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发表时间：
2018-01-01
影响因子：
2.8
通讯作者：
Xing, Shuai
中科院分区：
文献类型：
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作者：
Liu, Jian-Hua;He, Long;Xing, Shuai
背景/目的：TLR/MyD88/NE-KB信号通路已成功用于治疗肾间质纤维化(RIF)。然而，确切的治疗机制仍不清楚。在这里，我们评估了TJ-M2010-2，一种抑制MyD88同源二聚化的小分子化合物，对缺血再灌注损伤(IRO)诱导的RIF的治疗效果。方法：在体法建立小鼠肾间质纤维化模型，并用TJ-M2010-2进行预防治疗。体外培养的HK-2细胞与转化生长因子-β1共同诱导EMT，并用TJ-M2010-2进行预处理。结果：与IRI组相比，TJ-M2010-2组肾间质纤维化明显减轻，肾功能损害明显减轻，TGE-β1、α-SMA、Vimentin表达减少。MMP2、MMP9表达增加，E-钙粘蛋白表达增加。此外，TJ-M2010‘2可阻断转化生长因子-β1诱导的HK-2细胞的EMT，表现为形态转化受阻、E-钙粘蛋白表达恢复和α-SMA表达受抑。此外，与转化生长因子-p1组相比，TJ-M2010-2组对TRAF6、p65和Snail的表达有明显的抑制作用，而对IKBA的表达有上调作用。结论：该MyD88抑制剂有可能成为改善RIF的潜在治疗药物。(C)2018年作者(S)，S.Karger AG，巴塞尔出版
Background/Aims: The TLR/MyD88/NE-KB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRO. Methods: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-p1 to induce EMT, and the cells were pretreated with TJ-M2010-2. Results: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGE-beta 1, a-SMA, vimentin. MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-beta 1-induced EMT was blocked by TJ-M2010'2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited a-SMA expression. In addition, compared to the TGF-p1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IKBa. Conclusion: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF. (C) 2018 The Auther(s) Published by S. Karger AG, Basel