Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway.
Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway.
复制标题
氙通过 miR-21 靶信号通路预防脓毒性急性肾损伤
DOI：
10.1097/ccm.0000000000001001
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发表时间：
2015-07
影响因子：
8.8
通讯作者：
Ding X
中科院分区：
文献类型：
--
作者：
Jia P;Teng J;Zou J;Fang Y;Wu X;Liang M;Ding X
脓毒性急性肾损伤是危重患者最常见和危及生命的并发症之一，目前尚无获批的有效治疗方法。我们已经证明氙通过抑制细胞凋亡对啮齿类动物的缺血再灌注损伤和肾毒性提供肾保护。本研究旨在探讨氙预处理对脓毒性急性肾损伤的影响及其机制。实验动物研究。大学研究实验室。实验用雄性C57 BL/6小鼠进行，10周龄，体重20-25 g。我们诱导脓毒性急性肾损伤的单次腹腔注射大肠杆菌脂多糖的剂量为20毫克/公斤。在脓毒性急性肾损伤发作前24小时，将小鼠暴露于70%氙或70%氮中2小时。使用锁核酸修饰的抗miR进行miR-21的体内敲低，检查miR-21在氙预处理赋予的肾保护中的作用，并分析miR-21信号通路。氙预处理提供了形态和功能的肾保护，其特征在于减轻肾小管损伤、细胞凋亡和炎症减少。此外，氙处理显著上调肾脏中miR-21的表达，抑制促炎因子程序性细胞死亡蛋白4的表达和核因子-κB活性，并增加白细胞介素-10的产生。同时，氙预处理还抑制了10号染色体上缺失的促凋亡蛋白磷酸酶和张力蛋白同源物的表达，激活了蛋白激酶B信号通路，随后增加了抗凋亡B细胞淋巴瘤-2的表达，抑制了caspase-3的活性。miR-21的敲低上调了其靶效应物程序性细胞死亡蛋白4和10号染色体上缺失的磷酸酶和张力蛋白同源物的表达，导致细胞凋亡增加，并加剧了脂多糖诱导的急性肾损伤。我们的研究结果表明，氙预处理通过激活miR-21靶信号通路保护脂多糖诱导的急性肾损伤。
Septic acute kidney injury is one of the most common and life-threatening complications in critically ill patients, and there is no approved effective treatment. We have shown xenon provides renoprotection against ischemia-reperfusion injury and nephrotoxicity in rodents via inhibiting apoptosis. Here, we studied the effects of xenon preconditioning on septic acute kidney injury and its mechanism. Experimental animal investigation. University research laboratory. Experiments were performed with male C57BL/6 mice, 10 weeks of age, weighing 20–25 g. We induced septic acute kidney injury by a single intraperitoneal injection of Escherichia coli lipopolysaccharide at a dose of 20 mg/kg. Mice were exposed for 2 hours to either 70% xenon or 70% nitrogen, 24 hours before the onset of septic acute kidney injury. In vivo knockdown of miR-21 was performed using locked nucleic acid-modified anti-miR, the role of miR-21 in renal protection conferred by the xenon preconditioning was examined, and miR-21 signaling pathways were analyzed. Xenon preconditioning provided morphologic and functional renoprotection, characterized by attenuation of renal tubular damage, apoptosis, and a reduction in inflammation. Furthermore, xenon treatment significantly upregulated the expression of miR-21 in kidney, suppressed proinflammatory factor programmed cell death protein 4 expression and nuclear factor-κB activity, and increased interleukin-10 production. Meanwhile, xenon preconditioning also suppressed the expression of proapoptotic protein phosphatase and tensin homolog deleted on chromosome 10, activating protein kinase B signaling pathway, subsequently increasing the expression of antiapoptotic B-cell lymphoma-2, and inhibiting caspase-3 activity. Knockdown of miR-21 upregulated its target effectors programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10 expression, resulted in an increase in apoptosis, and exacerbated lipopolysaccharide-induced acute kidney injury. Our findings demonstrated that xenon preconditioning protected against lipopolysaccharide-induced acute kidney injury via activation of miR-21 target signaling pathways.