Necrostatin-1 Attenuates Renal Ischemia and Reperfusion Injury via Meditation of HIF-1α/mir-26a/TRPC6/PARP1 Signaling
| العنوان: | Necrostatin-1 Attenuates Renal Ischemia and Reperfusion Injury via Meditation of HIF-1α/mir-26a/TRPC6/PARP1 Signaling |
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| المؤلفون: | Mei Mei, Qian-Guang Pan, Youmin Pu, Hong Liu, Hongwen Zhao, Mao-Zhi Tang, Xiongfei Wu, Yue He, Huhai Zhang, Bingbing Shen |
| المصدر: | Molecular Therapy. Nucleic Acids Molecular Therapy: Nucleic Acids, Vol 17, Iss, Pp 701-713 (2019) |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, miR-26a, Necroptosis, HIF-1α, TRPC6, necroptosis, Inflammation, medicine.disease_cause, Article, Nec-1, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, oxidative stress, Viability assay, Kidney, Renal ischemia, Chemistry, lcsh:RM1-950, medicine.disease, ischemic/reperfusion injury, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, medicine.anatomical_structure, inflammation, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Tumor necrosis factor alpha, medicine.symptom, Reperfusion injury, Oxidative stress |
| الوصف: | Necroptosis, oxidative stress, and inflammation are major contributors to the pathogenesis of ischemic acute kidney injury. Necrostatin-1 (Nec-1), an inhibitor of the kinase domain of receptor-interacting protein kinase-1 (RIP1), has been reported to regulate renal ischemia and reperfusion (I/R) injury; however, its underlying mechanism of action remains unclear. HK-2 cells were used to create an in vitro I/R model, in which the cells were subjected to hypoxia, followed by 2, 6, and 12 h of reoxygenation. For the in vivo study, a rat model of renal I/R was established in which samples of rat blood serum and kidney tissue were harvested after reperfusion to assess renal function and detect histological changes. Cell viability and necroptosis were analyzed using the Cell Counting Kit (CCK)-8 assay and flow cytometry, respectively. The expression levels of molecules associated with necroptosis, oxidative stress, and inflammation were determined by real-time PCR, western blotting, immunofluorescence staining, and ELISA. Luciferase and chromatin immunoprecipitation (ChIP) assays were performed to confirm the relevant downstream signaling pathway. We found that pretreatment with Nec-1 significantly decreased hypoxia-inducible factor-1α (HIF-1α) and miR-26a expression, as well as the levels of factors associated with necroptosis (RIP1, RIP3, and Sirtuin-2), oxidative stress (malondialdehyde [MDA], NADP+/NADPH ratio), and inflammation (interleukin [IL]-1β, IL-10, and tumor necrosis factor alpha [TNF-α]) in I/R injury cells and the rat model. However, these effects could be reversed by miR-26a overexpression or TRPC6 knockdown. Mechanistic studies demonstrated that HIF-1α directly binds to the promoter region of miR-26a, and that TRPC6 is a potential target gene for miR-26a. Our findings indicate that Nec-1 can effectively protect against renal I/R injury by inhibiting necroptosis, oxidative stress, and inflammation, and may exert its effects through mediation of the HIF-1α/miR-26a/TRPC6/PARP1 signaling pathway. Keywords: ischemic/reperfusion injury, Nec-1, HIF-1α, miR-26a, TRPC6, necroptosis, oxidative stress, inflammation |
| تدمد: | 2162-2531 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d71c54dbef9c7d1ff2cfcaa2fca87c78 https://pubmed.ncbi.nlm.nih.gov/31422287 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d71c54dbef9c7d1ff2cfcaa2fca87c78 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21622531 |
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