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

The role of RNA methylation on the sixth N atom of adenylate (mA) in acute kidney injury (AKI) is unknown. FTO (fat mass and obesity-associated protein) reverses the mA 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 model, human kidney proximal tubular cells (HK2 cells) were treated with cisplatin. We found that the cisplatin treatment reduces FTO expression and increases mA levels and MA aggravated renal damage and increased apoptosis in cisplatin-treated kidneys, phenotypes that were correlated with reduced FTO expression and increased mA levels. Moreover, MA promoted apoptosis in cisplatin-treated HK2 cells, which was correlated with the reduced FTO expression and increased mA in HK2 cells. FTO protein overexpression reduced mA levels and inhibited apoptosis in cisplatin-treated HK2 cells and also blocked the MA-induced increase in mA levels and apoptosis rates. In agreement, overexpression of the mA-generating methyltransferase-like 3 and 14 (METTL3 and METTL14) or siRNA-mediated FTO knockdown promoted apoptosis and enhanced mA levels in cisplatin-treated HK2 cells. MA increased p53 mRNA and protein levels in AKI both and , and FTO overexpression reduced p53 expression and reversed the MA-induced p53 increase in AKI. In conclusion, reduced renal FTO expression in cisplatin-induced AKI increases RNA mA levels and aggravates renal damages.