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Podocyte injury associated with albuminuria and diabetic nephropathy (DN) progression. N6-methyladenosine (m6A) is a common form of epigenetic modification in eukaryotic cells and is known to be associated with a variety of disease processes. Its role in podocyte injury of DN remains poorly studied. We observed a higher expression of fat mass and obesity-associated protein (FTO) both in diabetic mice and human kidneys and DN podocytes in vitro, and the level of FTO was correlated with lipid accumulation. Furthermore, we confirmed that two selective FTO demethylation inhibitors meclofenamic acid (MA) and diacerein (DIA) administration effectively ameliorated lipotoxicity-induced podocyte injury, evidenced by restored autophagy, inhibition of apoptosis and inflammation, as well as mitigating endoplasmic reticulum stress (ERS) and mitochondrial damage both in vitro and vivo model of DN. Mechanistically, FTO demethylation inhibitors downregulated Acetyl-CoA-carboxylase 1 (ACC1) levels in db/db mice and advanced glycation end product (AGE)-treated podocytes, subsequently decreased podocyte fatty acid accumulation. ACC1 was identified as a direct FTO target in which FTO stabilizes ACC1 mRNA with the mediation of YTH domain-containing family protein 2 (YTHDF2) in an m6A-dependent manner using m6A RNA immunoprecipitation-quantitative real-time PCR (MeRIP-qPCR) and dual-luciferase reporter gene assays. Collectively, our findings demonstrate an important role of FTO mediated-m6A modification of ACC1 contributed to s lipotoxicity-mediated injury of DN podocytes, which provide fresh insights into the therapeutic strategies for DN.
Chang et al. (Fri,) studied this question.