miR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1.
miR-3587 Inhibitor Attenuates Ferroptosis Following Renal Ischemia-Reperfusion Through HO-1.
复制标题
miR-3587 抑制剂通过 HO-1 减轻肾缺血再灌注后的铁死亡
DOI：
10.3389/fmolb.2021.789927
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发表时间：
2021
影响因子：
5
通讯作者：
Qian K
中科院分区：
文献类型：
--
作者：
Tao W;Liu F;Zhang J;Fu S;Zhan H;Qian K
肾缺血再灌注(IR)常见于危重患者，但目前尚无可靠或有效的治疗方法。铁下垂是细胞程序性死亡的一种形式，受谷胱甘肽过氧化物酶4(Gpx4)和血红素加氧酶-1(Hmox1)等关键基因调控，参与IR过程中肾小管上皮细胞的损伤。本研究旨在探讨参与肾IR后铁性下垂的miRNA-mRNA调控网络。利用生物信息学分析发现，Hmox1在肾脏IR损伤的早期显著上调，microRNA-3587(miR-3587)被确定为Hmox1的可能调节因子。在肾小管上皮细胞缺氧-复氧(HR)模型体系中应用miR-3587抑制剂后，HO-1蛋白(由Hmox1编码)的表达较HR组显著增加，同时Gpx4蛋白水平升高，细胞活力增强，丙二醛含量降低，Fe2+水平降低，线粒体膜电位恢复正常。透射电子显微镜显示线粒体脊减少或消失，线粒体膜外膜受损。荧光素酶报告基因检测证实miR-3587靶向Hmox1。总之，这些初步结果表明，抑制miR-3587促进HO-1上调，从而保护肾组织免受IR诱导的铁性下垂的影响。
Renal ischemia-reperfusion (IR) is frequently observed in patients who are critically ill, yet there are no reliable or effective approaches for the treatment of this condition. Ferroptosis, a form of programmed cell death, is regulated by key genes such as glutathione peroxidase 4 (GPX4) and heme oxygenase-1 (HMOX1) and participates in the injury of renal tubular epithelial cells during IR. This study aimed to investigate the miRNA-mRNA regulatory networks involved in ferroptosis following renal IR. Using bioinformatics analysis, HMOX1 was found to be significantly upregulated during the early stages of renal IR injury, and microRNA-3587 (miR-3587) was identified as a putative regulator of HMOX1. When a miR-3587 inhibitor was applied in a hypoxia-reoxygenation (HR) model system using renal tubular epithelial cells, HO-1 protein (encoded by HMOX1) expression was significantly increased relative to that observed in the HR group, with concomitant increases in GPX4 protein levels, enhanced cell viability, a reduction in malondialdehyde content, decreased Fe2+ level, and the restoration of normal mitochondrial membrane potential. Transmission electron microscopy showed a reduced or absent mitochondrial crest and a damaged mitochondrial outer membrane. Targeting of HMOX1 by miR-3587 was confirmed by luciferase reporter gene assay. In conclusion, these preliminary results indicate that inhibition of miR-3587 promotes HO-1 upregulation, thereby protecting renal tissues from IR-induced ferroptosis.