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      MicroRNA-21 Attenuates Renal Ischemia Reperfusion Injury via Targeting Caspase Signaling in Mice

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          Background: MicroRNAs (miR) have come into focus as powerful regulators of gene expression and potential diagnostic tools during renal ischemia reperfusion injury (IRI). The aim of this study was to investigate the molecular regulation and function of miR-21, and to analyze the relationship between caspases and miR-21 expression levels in an experimental model of renal IRI. Methods: IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion. The male BALB/c mice were randomly assigned to the following groups: pre-miR-21 + IRI group, antagomiR-21 + IRI group, PBS + IRI group, pre-miR-21 + sham operation group, antagomiR-21 + sham operation group, PBS + sham operation group. The pre-miR-21 or antagomiR-21 was administered intraperitoneally (200 ng/kg weight) 24 and 6 h before induction of ischemia. Renal function, histological damage, renal cell apoptosis proteins were evaluated at 24 h after reperfusion. Results: Mice upregulated miR-21 had lower plasma levels of blood urea nitrogen (BUN) and creatinine, lower histopathological scores and a decrease in programmed cell death 4 (PDCD4) mRNA and active caspase-3, caspase-8 proteins expressions. Conclusions: miR-21 is endowed with anti-apoptotic properties by suppressing the expression of PDCD4 gene and active caspase 3/8 fragments in the condition of renal IRI. miR-21 exerts significant functional protection in our renal murine model of IRI.

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          Most cited references 20

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          MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction.

          Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI.
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            MicroRNA-21 protects against the H(2)O(2)-induced injury on cardiac myocytes via its target gene PDCD4.

            Reactive oxygen species (ROS)-induced cardiac cell injury via expression changes of multiple genes plays a critical role in the pathogenesis of numerous heart diseases. MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate about 30% of the genes in a cell via degradation or translational inhibition of their target mRNAs. Currently, the effects of ROS on miRNA expression and the roles of miRNAs in ROS-mediated injury on cardiac myocytes are uncertain. Using quantitative real-time RT-PCR (qRT-PCR), we demonstrated that microRNA-21 (miR-21) was upregulated in cardiac myocytes after treatment with hydrogen peroxide (H(2)O(2)). To determine the potential roles of miRNAs in H(2)O(2)-mediated gene regulation and cellular injury, miR-21 expression was downregulated by miR-21 inhibitor and upregulated by pre-miR-21. H(2)O(2)-induced cardiac cell death and apoptosis were increased by miR-21 inhibitor and was decreased by pre-miR-21. Programmed cell death 4 (PDCD4) that was regulated by miR-21 and was a direct target of miR-21 in cardiac myocytes. Pre-miR-21-mediated protective effect on cardiac myocyte injury was inhibited in H(2)O(2)-treated cardiac cells via adenovirus-mediated overexpression of PDCD4 without miR-21 binding site. Moreover, Activator protein 1 (AP-1) was a downstream signaling molecule of PDCD4 that was involved in miR-21-mediated effect on cardiac myocytes. The results suggest that miR-21 is sensitive to H(2)O(2) stimulation. miR-21 participates in H(2)O(2)-mediated gene regulation and functional modulation in cardiac myocytes. miR-21 might play an essential role in heart diseases related to ROS such as cardiac hypertrophy, heart failure, myocardial infarction, and myocardial ischemia/reperfusion injury.
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              Identification of a microRNA signature of renal ischemia reperfusion injury.

              Renal ischemia reperfusion injury (IRI) is associated with significant morbidity and mortality. Given the importance of microRNAs (miRNAs) in regulating gene expression, we examined expression profiles of miRNAs following renal IRI. Global miRNA expression profiling on samples prepared from the kidneys of C57BL/6 mice that underwent unilateral warm ischemia revealed nine miRNAs (miR-21, miR-20a, miR-146a, miR-199a-3p, miR-214, miR-192, miR-187, miR-805, and miR-194) that are differentially expressed following IRI when compared with sham controls. These miRNAs were also differently expressed following IRI in immunodeficient RAG-2/common gamma-chain double-knockout mice, suggesting that the changes in expression observed are not significantly influenced by lymphocyte infiltration and therefore define a lymphocyte-independent signature of renal IRI. In vitro studies revealed that miR-21 is expressed in proliferating tubular epithelial cells (TEC) and up-regulated by both cell-intrinsic and -extrinsic mechanisms resulting from ischemia and TGF-beta signaling, respectively. In vitro, knockdown of miR-21 in TEC resulted in increased cell death, whereas overexpression prevented cell death. However, overexpression of miR-21 alone was not sufficient to prevent TEC death following ischemia. Our findings therefore define a molecular fingerprint of renal injury and suggest miR-21 may play a role in protecting TEC from death.

                Author and article information

                Am J Nephrol
                American Journal of Nephrology
                S. Karger AG
                October 2014
                11 October 2014
                : 40
                : 3
                : 215-223
                aDepartment of Urology, The Second Affiliated Hospital of Nanchang University and bDepartment of Endocrinology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, PR China
                Author notes
                *Honglin Hu, Department of Urology, The Second Affiliated Hospital of Nanchang University, No.1 Minde Road, Nanchang, Jiangxi Province, 330006 (PR China), E-Mail
                368202 Am J Nephrol 2014;40:215-223
                © 2014 S. Karger AG, Basel

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                Page count
                Figures: 5, Pages: 9
                Original Report: Laboratory Investigation


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