Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.
Pharmacological inhibition of MyD88 homodimerization counteracts renal ischemia reperfusion-induced progressive renal injury in vivo and in vitro.
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MyD88 同二聚化的药理学抑制可抵消体内和体外肾缺血再灌注诱导的进行性肾损伤
DOI：
10.1038/srep26954
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发表时间：
2016-06-01
影响因子：
4.6
通讯作者：
Zhou P
中科院分区：
文献类型：
--
作者：
Zhang LM;Liu JH;Xue CB;Li MQ;Xing S;Zhang X;He WT;Jiang FC;Lu X;Zhou P
髓样分化因子88（MyD 88）介导的先天性免疫激活参与了缺血再灌注（I/R）诱导的急性肾损伤（阿基）和慢性肾损伤。然而，由于还没有任何有效的治疗方法，MyD 88在预防和治疗肾缺血再灌注损伤（IRI）中的确切药理作用尚不清楚。我们设计了一种小分子化合物TJ-M2010-2，它抑制MyD 88同源二聚化。我们使用了一个建立的单侧I/R小鼠模型。所有通过单侧肾切除术进行80分钟缺血的小鼠在没有干预的情况下在5天内死亡。然而，单独用TJ-M2010-2治疗显著提高了存活率至58.3%。TJ-M2010-2与CD 154拮抗剂的共同治疗使存活率增加至100%。TJ-M2010-2可明显抑制TGF-β1诱导的肾小管上皮细胞的上皮-间质转化（EMT），并能显著减轻肾间质损伤。此外，TJ-M2010-2在体内和体外均显著抑制TLR/MyD 88信号转导。总之，我们的研究结果强调了MyD 88抑制剂在预防和治疗急性或慢性肾I/R损伤方面的有前途的临床潜力，以及双系统抑制策略在IRI诱导的阿基中的治疗功能。此外，MyD 88抑制通过抑制EMT来改善肾I/R损伤诱导的肾小管间质纤维化。
The activation of innate immunity via myeloid differentiation factor 88 (MyD88) contributes to ischemia reperfusion (I/R) induced acute kidney injury (AKI) and chronic kidney injury. However, since there have not yet been any effective therapy, the exact pharmacological role of MyD88 in the prevention and treatment of renal ischemia reperfusion injury (IRI) is not known. We designed a small molecular compound, TJ-M2010-2, which inhibited MyD88 homodimerization. We used an established unilateral I/R mouse model. All mice undergoing 80 min ischemia through uninephrectomy died within five days without intervention. However, treatment with TJ-M2010-2 alone significantly improved the survival rate to 58.3%. Co-treatment of TJ-M2010-2 with the CD154 antagonist increased survival rates up to 100%. Twenty-eight days post-I/R of 60 min ischemia without nephrectomy, TJ-M2010-2 markedly attenuated renal interstitial and inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. Furthermore, TJ-M2010-2 remarkably inhibited TLR/MyD88 signaling in vivo and in vitro. In conclusion, our findings highlight the promising clinical potential of MyD88 inhibitor in preventing and treating acute or chronic renal I/R injuries, and the therapeutic functionality of dual-system inhibition strategy in IRI-induced AKI. Moreover, MyD88 inhibition ameliorates renal I/R injury-induced tubular interstitial fibrosis by suppressing EMT.