miR-21 Contributes to Xenon-conferred Amelioration of Renal Ischemia-Reperfusion Injury in Mice

Background: MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. Methods: Mice were exposed for 2h to either 70% xenon, or 70% nitrogen, 24h 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. Results: 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, 24h after ischemia-reperfusion (1.37 +/- 0.28 vs. 0.81 +/- 0.14mg/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-1 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-1. Conclusions: These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning.