Metformin attenuates O-GlcNAc modification to improve renal function via AMPK/mTOR signaling in diabetic nephropathy.

Diabetic nephropathy is a growing global health challenge, significantly increasing the risks of hypertension and cardiovascular complications. Despite existing treatment options, none effectively promote renal repair or halt disease progression. We aimed to investigate the role of O-GlcNAc modification and the potential of Metformin as a therapeutic agent in diabetic nephropathy. In this study, we recruited diabetic nephropathy patients and treated them with Metformin. In addition, this research employed pharmacological and genetic methods to examine the impact of O-GlcNAc modification on diabetic nephropathy rat models and mesangial cells. Significant improvements in kidney function were observed in diabetic nephropathy patients treated with Metformin, as evidenced by reduced serum biomarkers and decreased mesangial matrix expression in renal biopsies. In the rat models, OSMI-1 treatment led to reduced renal fibrosis, inflammation, and pathological damage. Mechanistic investigations revealed that Metformin inhibits O-GlcNAc modifications, attenuates mesangial cell hypertrophy, and exerts its therapeutic effects through the AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. These findings highlight Metformin as a promising therapeutic candidate for diabetic nephropathy. The study also sheds light on the novel role of O-GlcNAc modification in the pathogenesis of diabetic nephropathy, suggesting that targeting O-GlcNAc modifications could be a potential therapeutic strategy for diabetic nephropathy.