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MiR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

ABSTRACT: The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-alpha (HIF-1?) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1? and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both kinds of rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, especially in renal tubular cells. A similar increase was observed in hypoxia-treated human renal tubular HK-2 cells. We also verified that miR-210 can directly suppress HIF-1? expression by targeting the 3' untranslated region (UTR) of HIF-1? mRNA in HK-2 cells in severe hypoxia. Accordingly, miR-210 overexpression caused significant inhibition of the HIF-1? pathway and attenuated apoptosis caused by hypoxia, while miR-210 knockdown exerted the opposite effect. Taken together, our findings verify that miR-210 is involved in the molecular response in hypoxic kidney lesions in vivo and attenuates hypoxia-induced renal tubular cell apoptosis by targeting HIF-1? directly and suppressing HIF-1? pathway activation in vitro.

SUBMITTER: Liu LL

PROVIDER: S-EPMC5653737 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

Liu Li-Li LL Li Dahu D He Yun-Ling YL Zhou Yan-Zhao YZ Gong Sheng-Hui SH Wu Li-Ying LY Zhao Yong-Qi YQ Huang Xin X Zhao Tong T Xu Lun L Wu Kui-Wu KW Li Ming-Gao MG Zhu Ling-Ling LL Fan Ming M

Molecular medicine (Cambridge, Mass.) 20171016

The kidney is vulnerable to hypoxia-induced injury. One of the mechanisms underlying this phenomenon is cell apoptosis triggered by hypoxia-inducible factor-1-alpha (HIF-1α) activation. MicroRNA-210 (miR-210) is known to be induced by HIF-1α and can regulate various pathological processes, but its role in hypoxic kidney injury remains unclear. Here, in both kinds of rat systemic hypoxia and local kidney hypoxia models, we found miR-210 levels were upregulated significantly in injured kidney, esp ...[more]

PMID: 29387863

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Project description:Cardiac shock wave therapy (SWT) has been described as a novel therapeutic strategy that is able to alleviate myocardial ischemic injury. microRNA (miRNA/miR)?210 plays a cytoprotective role in cardiomyocytes in response to hypoxia by regulating cell apoptosis. The aim of the present study was to investigate whether cardiac SWT could protect cardiomyocytes from hypoxia?induced injury by regulating miR?210 expression. The murine adult cardiomyocyte cell line HL?1 was incubated for 5 h in hypoxic conditions, followed by reoxygenation for 12 h and treatment with SWT immediately following hypoxia in the present study. The cell viability was determined using an MTS assay. Western blot analyses were performed in order to detect cell signaling changes. Reactive oxygen species production was detected using dihydroethidium staining, and malondialdehyde levels were measured using the thiobarbituric acid method. miRNA and mRNA expression levels were confirmed via reverse transcription?quantitative PCR. Apoptosis was evaluated by means of flow cytometry. HL?1 cells were then transfected with miR?210 mimics or inhibitors in order to alter miR?210 expression levels, and the effects on HL?1 cells were determined. Hypoxia led to elevated oxidative stress, enhanced cell apoptosis and upregulated miR?210 expression levels in HL?1 cells, while SWT could alleviate hypoxia?induced cell injury and further promote miR?210 expression. miR?210 overexpression decreased apoptosis and oxidative stress during hypoxic stress in HL?1 cells, whereas inhibition of miR?210 increased cell apoptosis and promoted oxidative stress. Furthermore, miR?210 inhibition could reverse the effects of SWT on HL?1 cells. Finally, the mRNA analysis revealed that SWT significantly attenuated apoptosis?inducing factor mitochondrion?associated 3 and caspase 8 associated protein 2 mRNA expression levels in cardiomyocytes exposed to hypoxia, which were two targets of miR?210. SWT could exert cardioprotective effects against hypoxia?induced cardiac injury by modulating miR?210.

Project description:Background Few reports have addressed the mechanism by which microRNA miR-10b-5p regulates post-myocardial infarction (post-MI) cardiomyocyte apoptosis under hypoxic conditions. Methods and Results C57BL/6 mice underwent surgical ligation of the left anterior descending artery to create an MI or ischemia/reperfusion animal model. The expression of miR-10b-5p, PTEN (phosphatase and tensin homolog), and HIF-1? (hypoxia-inducible factor 1?) was detected in infarct border zone tissues at various time points. After precordial injections of the negative control or miR-10b-5p, overexpression lentiviruses were made in the areas surrounding the MI sites at 1 week, and myocardial infarct size, cardiac function, and cardiomyocyte apoptosis were examined. A miR-10b-5p mimic was transfected into primary mouse cardiomyocytes to analyze its effects on cardiomyocyte apoptosis and PTEN expression. Meanwhile, PTEN as a target of miR-10b-5p was verified via luciferase reporter gene assays. Cotransfection of miR-10b-5 and PTEN verified the relationship between miR-10b-5 and PTEN. Under hypoxic stress, the expression of HIF-1? and miR-10b-5p was examined. The results showed that miR-10b-5p expression was markedly reduced in the infarct border zone. Overexpression of miR-10b-5p in the murine model of MI significantly reduced MI size, improved cardiac function, and inhibited apoptosis. Overexpression of miR-10b-5p in vitro antagonized hypoxia-induced cardiomyocyte apoptosis and specifically inhibited the expression of the apoptosis-related gene PTEN, but overexpression of PTEN weakened these effects. We also found that hypoxia-induced accumulation of HIF-1? resulted in decreased expression of miR-10b-5p. Interfering with the activation of the HIF-1? signaling pathway promoted Pri-miR-10b and miR-10b-5p expression and inhibited PTEN expression. Conclusions MicroRNA miR-10b-5p antagonizes hypoxia-induced cardiomyocyte apoptosis, indicating that miR-10b-5p may serve as a potential future clinical target for the treatment of MI.

Project description:Endometriosis is associated with benign but adversely developed cysts in the extrauterine environment. The oxidative imbalanced environment induces DNA damage and affects cell cycle progression of endometrial stromal cells (ESCs) and endometrial epithelial cells, but how endometriotic cells maintain proliferation in the presence of oxidative stress is not clear. Growing evidence has indicated that the ectopic hypoxic microenvironment and oxidative stress can stimulate the growth of endometriotic cells, which is mainly due to the increase of HIF-1α. We found that the master hypoxia-associated miRNA miR-210-3p was increased in stromal and glandular cells of ectopic lesions compared with that of eutopic and normal endometria and was consistent with the expression of HIF-1α and the local oxidative stress-induced DNA damage predictor 8-OHdG. Moreover, miR-210-3p was upregulated in ESCs and Ishikawa cells under hypoxic conditions but not in normoxic culture. Knockdown of miR-210-3p induced a G2/M arrest of ESCs and Ishikawa cells under hypoxia, while no effect was found under normoxia. BARD1 was identified as a target of miR-210-3p. BARD1 expression was decreased in endometriotic tissues compared with eutopic and normal endometria and negatively correlated with the expression of miR-210-3p. Multivariate regression analysis showed that BARD1 downregulation could serve as an indicator for endometriotic severity. Our results suggest that miR-210-3p attenuates the G2/M cell cycle checkpoint by inactivating BRCA1 complex function in response to DNA damage under hypoxia via targeting the 3' untranslated region of BARD1 mRNA. Endometriotic mouse model experiments showed that intraperitoneal injection of the miR-210-3p inhibitor or vitamin C suppressed the growth of endometriotic lesions. Together, our results demonstrate that endometriotic cells inhibit BARD1/BRCA1 function by upregulating miR-210-3p, which might be the underlying mechanism for endometriotic cell maintenance of growth in oxidative stress. Furthermore, inhibition of miR-210-3p and administration of vitamin C are promising approaches for the treatment of endometriosis.

Project description:Background and Objective: Glucose fluctuation (GF) has been reported to induce renal injury and diabetic nephropathy (DN). However, the mechanism still remains ambiguous. Mitochondrial energy metabolism, especially aerobic glycolysis, has been a hotspot of DN research for decades. The activation of HIF-1α/miR210/ISCU/FeS axis has provided a new explanation for aerobic glycolysis. Our previous studies indicated quercetin as a potential therapeutic drug for DN. This study aims to evaluate levels of aerobic glycolysis and repressive effect of quercetin via HIF-1α/miR210/ISCU/FeS axis in a cell model of GF. Methods: The mouse glomerular mesangial cells (MCs) were exposed in high or oscillating glucose with or without quercetin treatment. Cell viability was measured by CCK8 assay. Aerobic glycolysis flux was evaluated by lactate acid, pH activity of PFK. Apoptosis level was confirmed by Annexin V-APC/7-AAD double staining and activity of caspase-3. TNF-α and IL-1β were used to evaluate inflammation levels. Results: GF deteriorated inflammation damage and apoptosis injury in MCs, while quercetin could alleviate this GF-triggered cytotoxicity. GF intensified aerobic glycolysis in MCs and quercetin could inhibit this intensification in a dose-dependent manner. Quercetin prevented activities of two FeS-dependent metabolic enzymes, aconitase, and complex I, under GF injury in MCs. The mRNA expression and protein contents of HIF-1α were increased after GF exposure, and these could be alleviated by quercetin treatment. Knockdown of ISCU by siRNA and Up-regulating of miR-210 by mimic could weaken the effects of quercetin that maintained protein levels of ISCU1/2, improved cell viability, relieved inflammation injury, decreased apoptosis, and reduced aerobic glycolysis switch in MCs. Conclusion: Quercetin antagonizes GF-induced renal injury by suppressing aerobic glycolysis via HIF-1α/miR-210/ISCU/FeS pathway in MCs cell model. Our findings contribute to a new insight into understanding the mechanism of GF-induced renal injury and protective effects of quercetin.

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MiR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

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miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha.

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