Wang Jian, Ishfaq Muhammad, Xu Liang, Xia Chunli, Chen Chunli, Li Jichang
College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China.
Front Pharmacol. 2019 May 15;10:517. doi: 10.3389/fphar.2019.00517. eCollection 2019.
Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N-Methyladenosine (mA) 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 μM colistin with or without METTL3 overexpression. Cells injury, mA assay, oxidative stress and apoptosis were examined. Levels of mA are decreased after colistin treatment in mRTECs. METTL3 is the major factor involved in abnormal mA 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 mA-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/mA in colistin-induced nephrotoxicity and provide a new insight on mA modification in drug induced toxicity.
黏菌素的肾毒性是限制其临床应用的主要因素。然而，黏菌素诱导肾毒性的确切机制仍不清楚。N-甲基腺苷（mA）修饰参与了许多生物学过程，但其在黏菌素诱导肾毒性中的作用尚待阐明。用200μM黏菌素处理小鼠肾小管上皮细胞（mRTECs），同时过表达或不过表达METTL3。检测细胞损伤、mA检测、氧化应激和细胞凋亡情况。黏菌素处理后mRTECs中的mA水平降低。METTL3是参与异常mA修饰的主要因素。过表达METTL3对黏菌素诱导的氧化应激和细胞凋亡起保护作用。此外，METTL3与微处理器蛋白DGCR8相互作用，并以mA依赖的方式正向调节miR-873-5p的成熟过程。进一步实验表明，miR-873-5p可调节Keap1-Nrf2通路以抵抗黏菌素诱导的氧化应激和细胞凋亡。这些研究揭示了METTL3/mA在黏菌素诱导肾毒性中的重要作用，并为药物诱导毒性中的mA修饰提供了新的见解。
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