FTO-mediated m6A modification alleviates diabetic nephropathy progression by downregulating the CYP2J3/Smurf2 axis.

Authors

Yinhao Liu, Chaohui Liu, Yuqing Chen, Tengjie Guo, Ke Cheng, Lizhen Chen

Published in

Scientific reports. Jul 08, 2026. Epub Jul 08, 2026.

Abstract

The m6A demethylase FTO is implicated in epigenetic regulation, yet its specific mechanism in diabetic nephropathy (DN) remains unclear. This study investigates whether FTO mitigates DN progression by regulating the CYP2J3/Smurf2 axis. Mouse glomerular mesangial SV40-MES-13 cells were treated with high glucose (HG). Gene and protein expressions were assessed via qPCR and Western blot. MeRIP-qPCR and RIP assays evaluated m6A modifications and FTO-CYP2J3 mRNA binding. The CYP2J3-Smurf2 interaction was detected via immunofluorescence and co-Immunoprecipitation. Following FTO and CYP2J3 overexpression (OE), cell viability and fibrotic markers (p-Smad7/Smad7, TGF-β1, α-SMA, Fibronectin) were measured. In vivo validation was performed in DN mice, with evaluation of renal function alongside histological and immunohistochemical analyses. FTO was significantly downregulated in HG-treated cells. FTO directly interacted with CYP2J3 mRNA, and FTO OE decreased both the m6A modification level and the overall expression of CYP2J3. This reduction successfully suppressed the targeted binding between CYP2J3 and Smurf2. Functionally, FTO OE reversed HG-induced cell viability changes and inhibited the expression of downstream fibrotic proteins. Rescue experiments confirmed that CYP2J3 OE reversed the anti-fibrotic protective effects of FTO. In vivo, FTO OE significantly improved renal function parameters and attenuated pathological tissue injury and extracellular matrix accumulation in DN mice, effects which were counteracted by the co-overexpression of CYP2J3. FTO alleviates HG-induced renal fibrosis and overall DN progression by downregulating CYP2J3 via m6A modification, thereby reducing the CYP2J3-Smurf2 interaction.

PMID:
42420394
Bibliographic data and abstract were imported from PubMed on 09 Jul 2026.

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