METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway
METTL3/m6A/miRNA-873-5p Attenuated Oxidative Stress and Apoptosis in Colistin-Induced Kidney Injury by Modulating Keap1/Nrf2 Pathway
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METTL3/m(6)A/miRNA-873-5p 通过调节 Keap1/Nrf2 通路减轻粘菌素诱导的肾损伤中的氧化应激和细胞凋亡
DOI：
10.3389/fphar.2019.00517
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发表时间：
2019-05-15
影响因子：
5.6
通讯作者：
Li, Jichang
中科院分区：
文献类型：
--
作者：
Wang, Jian;Ishfaq, Muhammad;Li, Jichang
粘菌素的肾毒性是限制其临床应用的主要因素。然而，粘菌素引起肾毒性的确切机制尚不清楚。n- 6-甲基腺苷（m(6)A）修饰与许多生物过程有关，然而，其在粘菌素诱导的肾毒性中的作用需要阐明。用200 μ M粘菌素处理小鼠肾小管上皮细胞（mRTECs）， METTL3过表达或不过表达。观察细胞损伤、m(6)A实验、氧化应激和细胞凋亡。多粘菌素治疗后，mrtec中m(6)A水平降低。METTL3是导致m(6)A异常修饰的主要因素。METTL3过表达对粘菌素诱导的氧化应激和细胞凋亡具有保护作用。此外，METTL3与微处理器蛋白DGCR8相互作用，并以m(6) a依赖的方式正向调节miR-873-5p成熟过程。进一步实验表明，miR-873-5p可调控Keap1-Nrf2通路，对抗粘菌素诱导的氧化应激和细胞凋亡。这些研究揭示了METTL3/m(6)A在粘菌素诱导肾毒性中的重要作用，并为研究m(6)A修饰在药物诱导毒性中的作用提供了新的思路。
Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N-6-Methyladenosine (m(6)A) modification has been implicated in many biological processes, however, its role in colistin-induced nephrotoxicity needs to be elucidated. Mouse renal tubular epithelial cells (mRTECs) were treated with 200 mu M colistin with or without METTL3 overexpression. Cells injury, m(6)A assay, oxidative stress and apoptosis were examined. Levels of m(6)A are decreased after colistin treatment in mRTECs. METTL3 is the major factor involved in abnormal m(6)A modification. METTL3 overexpression plays a protective role against colistin-induced oxidative stress and apoptosis. Moreover, METTL3 interacts with the microprocessor protein DGCR8 and positively modulates miR-873-5p mature process in an m(6)A-dependent manner. Further experiments show that miR-873-5p could regulate Keap1-Nrf2 pathway against colistin-induced oxidative stress and apoptosis. These studies revealed an important role of METTL3/m(6)A in colistin-induced nephrotoxicity and provide a new insight on m(6)A modification in drug induced toxicity.