title: Resveratrol inhibits renal interstitial fibrosis in diabetic nephropathy by regulating AMPK/NOX4/ROS pathway.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: He
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Jiachuan
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Nie
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Guan
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Tangli
authors.initials: T
authors.lastname: Xiao
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Daohai
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Yunjian
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China.
authors.forename: Jingbo
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury of PLA, Third Military Medical University, Chongqing, 400038, People's Republic of China.
authors.forename: Junping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, University of California, La Jolla, CA, USA.|Veterans Administration San Diego HealthCare System, La Jolla, CA, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Nephrology, Institute of Nephrology of Chongqing and Kidney Center of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, People's Republic of China. zhaojh@tmmu.edu.cn.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Zhao
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000074663:NADPH Oxidase 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D013267:Stilbenes; D000074663:NADPH Oxidase 4; C422943:Nox4 protein, mouse; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077185:Resveratrol
keywords: AMPK; Diabetic nephropathy; ERK 1/2; NOX; Reactive oxygen species; Resveratrol