DNA Methylation Of FTO Promotes Renal Inflammation By Enhancing M6A Of PPAR-α In Alcohol-induced Kidney Injury

Alcohol consumption is one of the risk factors for kidney injury.The underlying mechanism of alcohol-induced kidney injury remains largely unknown.We previously found that the kidney in a mouse model of alcoholic kidney injury had severe inflammation.In this study,we found that the administration of alcohol was associated with the activation of NLRP3 inflammatory complex and NF-κB pathway,and the production of inflammatory cytokines.Whole-genome methylation sequencing(WGBS)showed that the DNA encoding fat mass and obesity-associated protein(FTO)was significantly methylated in the alcoholic kidney.This finding was confirmed with the bisulfite sequencing(BSP),which showed that alcohol increased DNA methylation of FTO in the kidney.Furthermore,inhibition of DNA methyltransferases(DNMTs)by5-azacytidine(5-aza)reversed alcohol-induced kidney injury and decreased the m RNA and protein levels of FTO.Importantly,we found that FTO,the m6 A demethylase,epigenetically modified peroxisome proliferator activated receptor-α(PPAR-α)in a YTH domain family 2(YTHDF2)-dependent manner,which resulted in inflammation in alcoholic kidney injury models.In conclusion,our findings indicate that alcohol increases the methylation of PPAR-α m6 A by FTO-mediated YTHDF2 epigenetic modification,which ultimately leads to the activation of NLRP3 inflammasomes and NF-κB-driven renal inflammation in the kidney.These findings may provide novel strategies for preventing and treating alcoholic kidney diseases.