miR-146a is essential for lipopolysaccharide (LPS)-induced cross-tolerance against kidney ischemia/reperfusion injury in mice
miR-146a is essential for lipopolysaccharide (LPS)-induced cross-tolerance against kidney ischemia/reperfusion injury in mice
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miR-146a对于脂多糖（LPS）诱导的小鼠肾脏缺血/再灌注损伤的交叉耐受至关重要
DOI：
10.1038/srep27091
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发表时间：
2016-06-02
影响因子：
4.6
通讯作者：
Ding, Xiaoqiang
中科院分区：
文献类型：
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作者：
Dai, Yan;Jia, Ping;Ding, Xiaoqiang
MicroRNA-146a 是通过（Toll 样受体）TLR/NF-kappa B 途径参与内毒素耐受发展的最重要的 microRNA 之一。在本研究中，我们试图确定 miR-146a 在介导脂多糖 (LPS) 预处理对肾脏缺血/再灌注损伤的保护作用中的机制作用。在 LPS 治疗之前给予锁定核酸修饰的抗 miR-146a 可以降低 miR-146a 的表达，并完全否定 LPS 介导的针对肾缺血/再灌注损伤的保护作用。 miR-146a 的敲低导致肾小管损伤、促炎细胞因子和趋化因子表达以及中性粒细胞和巨噬细胞浸润的组织病理学评分显着升高。此外，miR-146a的敲低大大上调了IL-1受体相关激酶（IRAK-1）和肿瘤坏死因子（TNF）受体相关因子6（TRAF6）的蛋白水平，它们是miR-146a的已知靶基因，导致NF-κB的激活。最后，NF-κB p65/p50和核转位的升高 caspase-3 表达、胞浆 IkB α 和 BcL-xL 降解以及肾小管细胞凋亡的显着加剧与 miR-146a 表达呈负相关。综上所述，我们的结果表明，miR146a 通过抑制 NF-κ B 激活和促炎基因表达，负向调节急性炎症反应，发挥肾脏保护作用。
MicroRNA-146a is one of most important microRNAs involved in development of endotoxin tolerance via (toll-like receptors) TLRs/NF-kappa B pathway. In this study, we sought to identify the mechanistic role of miR-146a in mediating the protective effect of lipopolysaccharide (LPS) pretreatment on kidney ischemia/reperfusion injury. A locked nucleic acid-modified anti-miR-146a given before LPS treatment knocked down miR-146a expression and completely negated LPS-mediated protection against kidney ischemia/reperfusion injury. Knockdown of miR-146a resulted in significantly higher histopathological scores for tubular damage, expression of proinflammatory cytokines and chemokines, and neutrophil and macrophage infiltration. Furthermore, knockdown of miR-146a greatly up-regulated the protein levels of IL-1 receptor-associated kinase (IRAK-1) and tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which are known target genes of miR-146a, leading to activation of NF-kappa B. Finally, elevation of nuclear translocation of NF-kappa B p65/p50 and caspase-3 expression, degradation of cytosolic IkB alpha and BcL-xL, and substantially exacerbation of tubular cell apoptosis were inversely correlated with miR-146a expression. Taken together, our results identify that miR146a exerts a kidney protective effect through negative regulation of acute inflammatory response by suppressing NF-kappa B activation and proinflammatory genes expression.