Jia Ping, Teng Jie, Zou Jianzhou, Fang Yi, Wu Xie, Liang Mingyu, Ding Xiaoqiang
1Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China. 2Kidney and Dialysis Institute of Shanghai, Shanghai, China. 3Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China. 4Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Crit Care Med. 2015 Jul;43(7):e250-9. doi: 10.1097/CCM.0000000000001001.
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.
脓毒症急性肾损伤是重症患者中最常见且危及生命的并发症之一，目前尚无获批的有效治疗方法。我们已表明，氙气通过抑制细胞凋亡，对啮齿动物的缺血再灌注损伤和肾毒性具有肾脏保护作用。在此，我们研究了氙气预处理对脓毒症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。
实验使用10周龄、体重20 - 25克的雄性C57BL/6小鼠。
通过单次腹腔注射剂量为20毫克/千克的大肠杆菌脂多糖诱导脓毒症急性肾损伤。在脓毒症急性肾损伤发作前24小时，将小鼠暴露于70%氙气或70%氮气中2小时。使用锁核酸修饰的抗miR对miR - 21进行体内敲低，研究miR - 21在氙气预处理赋予的肾脏保护中的作用，并分析miR - 21信号通路。
氙气预处理提供了形态学和功能性肾脏保护，其特征为肾小管损伤减轻、细胞凋亡减少以及炎症减轻。此外，氙气治疗显著上调了肾脏中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，氙气预处理还抑制了促凋亡蛋白10号染色体缺失的磷酸酶和张力蛋白同源物的表达，激活蛋白激酶B信号通路，随后增加抗凋亡蛋白B细胞淋巴瘤 - 2的表达，并抑制半胱天冬酶 - 3活性。敲低miR - 21上调了其靶效应分子程序性细胞死亡蛋白4和10号染色体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，并加重脂多糖诱导的急性肾损伤。
我们的研究结果表明，氙气预处理通过激活miR - 21靶信号通路，对脂多糖诱导的急性肾损伤具有保护作用。
