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

TY - JOUR

T1 - Metformin attenuates O-GlcNAc modification to improve renal function via AMPK/mTOR signaling in diabetic nephropathy

AU - Qi, Bingxue

AU - Chen, Yang

AU - Lan, Yuejiao

AU - Lou, Yan

AU - Cui, Pingli

AU - Yuan, Ruichen

AU - Zhao, Jingbo

AU - Chai, Siyang

AU - Kang, Li

AU - Zhou, Guannan

AU - Liu, Shuangshuang

AU - Lu, Xiaodan

AU - Huang, Li-Hao

N1 - Copyright: © 2025 The Authors

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

KW - diabetic nephropathy

KW - mesangial cell hypertrophy

KW - renal fibrosis

KW - AMPK/mTOR

KW - O-GlcNAc modification

UR - https://www.scopus.com/pages/publications/105023418945

U2 - 10.1016/j.jbc.2025.110909

DO - 10.1016/j.jbc.2025.110909

M3 - Article

C2 - 41203135

SN - 0021-9258

VL - 301

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 12

M1 - 110909

ER -