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

Abstract

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-induced p53 increase in AKI. In conclusion, reduced renal FTO expression in cisplatin-induced AKI increases RNA m 6 A levels and aggravates renal damages.

FTO alleviates Aβ1-40 induced retinal pigment epithelium degeneration via PKA/CREB signaling pathway

“…Therefore, we chose 100μM MA1 by CCK8 cell viability test to reduce the side effect of MA1 on RPE cells (Figure 3a and b). Previous study showed that MA could effectively inhibited FTO's function and expression, in uencing its downstream pathways [35]. In our study, we used MA1 to inhibit FTO demethylation in Aβ induced damaging model.…”

Resveratrol Attenuates Aflatoxin B1-Induced ROS Formation and Increase of m6A RNA Methylation

“…Interestingly, a novel study supported that silencing METTL3 could inhibit apoptosis in hypoxia/reoxygenation-treated cardiomyocytes [37]. Overexpression of METTL3 or knockdown of FTO enhanced m 6 A levels and activated apoptosis in cisplatin-treated human kidney proximal tubular cells [38]. Conversely, METTL3 knockdown could active caspase-3 in gastric cancer cells [39].…”

Integrated Analysis of m6A Methylome in Cisplatin-Induced Acute Kidney Injury and Berberine Alleviation in Mouse

“…Previous studies have shown that m6A modification can regulate cellular responses to stimuli by affecting mRNA transcription, splicing, localization, translation, stability, and posttranscriptional regulation of gene expression at the RNA level (Zhou et al, 2015;Fry et al, 2017). Evidence (Anders et al, 2018;Wang Y. et al, 2019;Zhou P. et al, 2019;Li et al, 2020;Liu et al, 2020;Xu et al, 2020) also suggests a strong relationship between m6A modification and kidney disease, thereby revealing an important biological role for m6A in the regulation of kidney injury. In this study, a reliable cisplatin-induced AKI model was established in mice, and the model was tested by analyzing Scr, BUN, and kidney section images.…”

“…Another study reported that cisplatin treatment reduced FTO expression and increased m6A levels in vivo and in vitro. They also found that inhibiting FTO by meclofenamic acid aggravated renal damage and increased apoptosis in cisplatin-treated kidneys (Zhou P. et al, 2019). METTL14 is elevated in people with AKI (Xu et al, 2020).…”