Meclofenamic acid promotes cisplatin-induced acute kidney injury by inhibiting fat mass and obesity-associated protein-mediated m 6 A abrogation in RNA

• Published in: The Journal of biological chemistry Vol. 294; no. 45; p. 16908
• Main Authors: Zhou, Peihui, Wu, Ming, Ye, Chaoyang, Xu, Qingqing, Wang, Li
• Format: Journal Article
• Language: English
• Published: United States 08.11.2019
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adipose Tissue - pathology; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - deficiency; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism; Animals; Apoptosis - drug effects; Cell Line; Cisplatin - pharmacology; Drug Synergism; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Humans; Male; Meclofenamic Acid - pharmacology; Mice; Mice, Inbred C57BL; RNA - chemistry; RNA - metabolism; Tumor Suppressor Protein p53 - metabolism; Fat mass and obesity-associated protein, FTO; RNA modification; kidney; N6-methyladenosine, m6A; acute kidney injury, AKI; cell signaling; apoptosis; cisplatin; RNA methylation; caspase; p53
• ISSN: 1083-351X

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