miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice.
miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice.
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miR-21 有助于氙改善小鼠肾缺血再灌注损伤。
DOI：
10.1097/aln.0b013e318298e5f1
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发表时间：
2013-09
期刊：
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;Zhang X;Bosnjak ZJ;Liang M;Ding X
MicroRNAs参与调节多种生理和疾病过程。MicroRNAs在麻醉药提供的器官保护中的体内作用尚不清楚。小鼠暴露于70%氙气或70%氮气中2 h，24 h后造成肾缺血再灌注损伤。通过体内miR-21基因敲除和miR-21靶通路分析，研究了miR-21在氙气延迟预适应所致肾脏保护中的作用。氙气预适应对肾缺血再灌注损伤有形态和功能保护作用(n=6)，其特征是减轻肾小管损伤、细胞凋亡和氧化应激。氙气预处理显著增加小鼠肾脏miR-21的表达。氙气预适应前给予锁定核酸修饰的抗miR-21能有效地击倒miR-21，并加重随后的肾缺血再灌注损伤。抗miR-21和缺血再灌注损伤组小鼠在缺血再灌注后24 h血清肌酐水平显著高于反义寡核苷酸组(1.37±0.28 vs.0.81±0.14 mg/dl；n=5；P<；0.05)。MiR-21基因敲除后，肾小管上皮细胞程序性死亡蛋白4和10号染色体上缺失的磷酸酶和张力蛋白同源物表达显著上调，磷酸化蛋白激酶B表达显著下调，肾小管上皮细胞凋亡率增加。此外，氙气预适应以时间依赖的方式上调低氧诱导因子-1α及其下游效应因子血管内皮生长因子。MiR-21基因敲除后，缺氧诱导因子-1α的表达显著降低。这些结果表明miR-21参与了氙气预适应的肾脏保护作用。
MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti–miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti–miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 ± 0.28 vs. 0.81 ± 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1α and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia-inducible factor-1α. These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.