Delayed ischemic preconditioning contributes to renal protection by upregulation of miR-21

Abstract

Delayed ischemic preconditioning effectively protects kidneys from ischemia-reperfusion injury but the mechanism underlying renal protection remains poorly understood. Here we examined the in vivo role of microRNA miR-21 in the renal protection conferred by delayed ischemic preconditioning in mice. A 15 minute renal ischemic preconditioning significantly increased the expression of miR-21 by 4 hours and substantially attenuated ischemia-reperfusion injury induced 4 days later. A locked nucleic acid-modified anti-miR-21 given at the time of ischemic preconditioning knocked down miR-21 and significantly exacerbated subsequent ischemia-reperfusion injury in the mouse kidney. Knockdown of miR-21 resulted in significant upregulation of programmed cell death protein 4, a pro-apoptotic target gene of miR-21, and substantially increased tubular cell apoptosis. Hypoxia inducible factor-1α in the kidney was activated after ischemic preconditioning and blockade of its activity with a decoy abolished the up-regulation of miR-21 in cultured human renal epithelial cells treated with the inducer cobalt chloride. In the absence of ischemic preconditioning, knockdown of miR-21 alone did not significantly affect ischemia-reperfusion injury in the mouse kidney. Thus, upregulation of miR-21 contributes to the protective effect of delayed ischemic preconditioning against subsequent renal ischemia-reperfusion injury.

MicroRNA-21 in the pathogenesis of acute kidney injury

“…On the other hand, knockdown of miR-21 resulted in signifi cant up-regulation of PCDP4 and a substantial increase in tubular cell apoptosis. The same study also showed that miR-21 performed a renal protective effect by further delaying IPC against subsequent renal IRI (Xu et al 2012) . Therefore, up-regulation of miR-21 during a short period of ischemia followed by reperfusion can activate endogenous defense mechanisms that protect against a subsequent, sustained ischemic insult; however, imbalanced expression may contribute to a serious irreversible outcome.…”

“…MiR-21 has been reported to promote such proliferation and act as a strong anti-apoptotic factor to inhibit cell death (Chan et al, 2005;Cheng et al, 2010;Godwin et al, 2010). Recent fi ndings have also shown that up-regulation of miR-21 contributed to a reduction in renal cell apoptosis and it also consistently shows protective effects against renal IRI after ischemic preconditioning (IPC) (Xu et al, 2012).…”

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“…This is in contrast to a previous study in which a 15-minute IPC regimen attenuated IRI induced 4 days later, associated with up-regulated miR-21 and hypoxiainducible factor 1α expression. 16 Similar to our study, this previous study used an IPC regimen of 15 minutes of continuous ischemia, but the extended period of 4 days between IPC and IRI may be key in terms of understanding the different outcomes. A beneficial effect after this extended recovery may support improvements in tissue robustness to subsequent injury that take hours rather than minutes to set in place.…”

“…15 Another study identified the importance of miR-21 in a mouse model of IRI and IPC. 16 In that study, 15 minutes of localized IPC significantly increased miR-21 expression, resulting in attenuation of IRI 4 days later, whereas knockdown of miR-21 significantly increased tubular cell apoptosis. 16 The purpose of this study was to determine whether a 15-minute localized IPC regimen attenuated injury in a rat model of unilateral IRI.…”

“…16 In that study, 15 minutes of localized IPC significantly increased miR-21 expression, resulting in attenuation of IRI 4 days later, whereas knockdown of miR-21 significantly increased tubular cell apoptosis. 16 The purpose of this study was to determine whether a 15-minute localized IPC regimen attenuated injury in a rat model of unilateral IRI. To this end, we evaluated histologic damage and analyzed the expression of selected acute kidney injury markers ( [20][21][22][23] and miR-21.…”