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

Area of Science:

• Epigenetics
• Molecular Biology
• Nephrology

Background:

• The m6A demethylase FTO plays a role in epigenetic regulation, but its precise mechanism in diabetic nephropathy (DN) is not fully understood.
• Investigating FTO's role is crucial for understanding and potentially treating DN, a common complication of diabetes.

Purpose of the Study:

• To determine if FTO mitigates DN progression by regulating the CYP2J3/Smurf2 axis.
• To elucidate the molecular mechanisms underlying FTO's function in DN.

Main Methods:

• Utilized high glucose (HG)-treated mouse glomerular mesangial cells (SV40-MES-13) and in vivo DN mouse models.
• Assessed gene and protein expression via qPCR and Western blot; evaluated m6A modification and FTO-CYP2J3 mRNA binding using MeRIP-qPCR and RIP assays.
• Investigated CYP2J3-Smurf2 interaction via immunofluorescence and co-Immunoprecipitation; performed overexpression studies and functional rescue experiments.

Main Results:

• FTO was downregulated in HG-treated cells; FTO directly bound to CYP2J3 mRNA, reducing its m6A modification and expression.
• FTO overexpression suppressed CYP2J3-Smurf2 interaction, reversed HG-induced changes in cell viability, and inhibited fibrotic markers.
• In vivo, FTO overexpression improved renal function and attenuated kidney injury and extracellular matrix accumulation in DN mice.

Conclusions:

• FTO alleviates high glucose-induced renal fibrosis and DN progression by downregulating CYP2J3 via m6A modification.
• This mechanism involves reducing the CYP2J3-Smurf2 interaction, highlighting a novel therapeutic target for DN.