Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2016-12, Vol.94 (12), p.1359-1371
• Main Authors: He, Ting, Xiong, Jiachuan, Nie, Ling, Yu, Yanlin, Guan, Xu, Xu, Xinli, Xiao, Tangli, Yang, Ke, Liu, Liang, Zhang, Daohai, Huang, Yunjian, Zhang, Jingbo, Wang, Junping, Sharma, Kumar, Zhao, Jinghong
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Antioxidants - pharmacology; Biomedical and Life Sciences; Biomedicine; Cell Differentiation - drug effects; Cell Line; Cell Proliferation - drug effects; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibrosis; Gene Expression Regulation; Glucose - pharmacology; Human Genetics; Internal Medicine; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Medicine; Myofibroblasts - cytology; Myofibroblasts - drug effects; Myofibroblasts - metabolism; NADPH Oxidase 4 - antagonists & inhibitors; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Original Article; Rats; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Stilbenes - pharmacology
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-016-1451-y

Renal interstitial fibrosis is a major pathologic feature of diabetic nephropathy, while the pathogenesis and therapeutic interventions of diabetic renal interstitial fibrosis are not well established. In this study, we first demonstrated that high glucose could induce renal fibroblast (NRK-49F) cell proliferation and activation to myofibroblasts, accompanied by a significant increase in the intracellular levels of reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). ROS-mediated ERK1/2 activation was found to play a crucial role in high glucose-induced fibroblast proliferation and activation. Resveratrol, like the NOX4-targeting small interfering RNA (siRNA), markedly inhibited high glucose-induced fibroblast proliferation and activation by reducing NOX4-derived ROS production. It was then revealed that the increase in the expression of NOX4 induced by high glucose was due to the inactivation of AMP-activated protein kinase (AMPK), which could be reversed by resveratrol. Further in vivo investigation demonstrated that resveratrol treatment significantly attenuated renal fibrosis in db/db mice, accompanied by an evident increase in phospho-AMPK and decrease in NOX4. In summary, our results suggest that high glucose can directly promote renal fibroblasts proliferation and activation in a ROS-dependent manner, and resveratrol is a potential therapeutic agent against diabetic renal fibrosis via regulation of AMPK/NOX4/ROS signaling. Key message Resveratrol inhibits high glucose-induced NRK cell activation by decreasing NOX4-derived ROS. Resveratrol inhibits high glucose-induced NOX4 expression in NRK cells via activation of AMPK. ROS-activated ERK1/2 signaling is involved in high glucose-induced NRK cell activation. Resveratrol attenuated renal fibrosis in db/db mice via regulation of AMPK/NOX4/ROS signaling.