Kidney Diseases · Published 2025-08-20 · DOI 10.1159/000547688
<p>Introduction: Diabetic nephropathy (DN) is a major cause of end-stage renal disease, characterized by podocyte injury and impaired autophagy. Epitranscriptomic mechanisms, particularly N6-methyladenosine (m6A) RNA modifications, have emerged as critical regulators in kidney disease, but their role in autophagy regulation within podocytes remains poorly understood. The aim of this study was to investigate the role of the m6A demethylase FTO in regulating podocyte autophagy and the pathogenesis of diabetic kidney disease (DKD), with a focus on its downstream effector ATF3. Methods: The study employed a multitiered approach involving human kidney biopsies from DN patients, in vitro podocyte models under high-glucose conditions, and podocyte-specific FTO knockout (iPFKO) mice. Key assessments included m6A immunoprecipitation sequencing to identify m6A-modified transcripts, RNA stability assays, Western blotting, immunofluorescence, transmission electron microscopy, and histological analysis. Autophagy flux was evaluated using LC3-II/LC3-I ratios and p62 accumulation. Results: FTO was selectively upregulated in podocytes from human DN samples and high-glucose-treated cells. FTO overexpression led to global m6A hypomethylation, especially affecting autophagy-related transcripts. ATF3 was identified as a hypomethylated, stabilized transcript whose expression was enhanced by FTO. Elevated ATF3 suppressed transcription of autophagy genes (e.g., LC3, ULK1, ATG5, Beclin1), impairing autophagy flux. FTO knockdown or ATF3 inhibition restored autophagy in vitro. In iPFKO mice, FTO deletion reduced ATF3 expression, preserved autophagy, and attenuated proteinuria, glomerular damage, and foot process effacement under diabetic conditions. Conclusions: FTO impairs podocyte autophagy in DKD via m6A demethylation-mediated stabilization of ATF3. Targeting the FTO-ATF3 axis may offer a promising therapeutic strategy to preserve podocyte integrity and mitigate DKD progression. </p>
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