Meclofenamic acid promotes cisplatin-induced acute kidney injury by inhibiting fat mass and obesity-associated protein-mediated m6A abrogation in RNA

作者：Peihui Zhou, Ming Wu, Chaoyang Ye, Qingqing Xu, Li Wang · 发表于：Journal of Biological Chemistry · 年份：2019 · DOI：10.1074/jbc.ra119.011009 · 被引用次数：72 · 研究领域：RNA modifications and cancer、Cancer-related gene regulation、Epigenetics and DNA Methylation

The role of RNA methylation on the sixth N atom of adenylate (m 6 A) in acute kidney injury (AKI) is unknown. FTO (fat mass and obesity-associated protein) reverses the m 6 A modification in cisplatin-induced AKI. Here, we aimed to determine FTO's role in AKI. We induced AKI in c57BL/6 mice by intraperitoneal cisplatin injection and treated the animal with vehicle or an FTO inhibitor meclofenamic acid (MA) for 3 days. Moreover, as an in vitro model, human kidney proximal tubular cells (HK2 cells) were treated with cisplatin. We found that the cisplatin treatment reduces FTO expression and increases m 6 A levels in vivo and in vitro . MA aggravated renal damage and increased apoptosis in cisplatin-treated kidneys, phenotypes that were correlated with reduced FTO expression and increased m 6 A levels. Moreover, MA promoted apoptosis in cisplatin-treated HK2 cells, which was correlated with the reduced FTO expression and increased m 6 A in HK2 cells. FTO protein overexpression reduced m 6 A levels and inhibited apoptosis in cisplatin-treated HK2 cells and also blocked the MA-induced increase in m 6 A levels and apoptosis rates. In agreement, overexpression of the m 6 A-generating methyltransferase-like 3 and 14 (METTL3 and METTL14) or siRNA-mediated FTO knockdown promoted apoptosis and enhanced m 6 A levels in cisplatin-treated HK2 cells. MA increased p53 mRNA and protein levels in AKI both in vitro and in vivo , and FTO overexpression reduced p53 expression and reversed the MA-...