title: High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol.
abstract: Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Lanyu
authors.initials: L
authors.lastname: Zhang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Pang
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.forename: Lihua
authors.initials: L
authors.lastname: Qian
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Junjie
authors.initials: J
authors.lastname: Zou
authors.forename: Jiaoyang
authors.initials: J
authors.lastname: Zheng
authors.forename: Linghui
authors.initials: L
authors.lastname: Yang
authors.forename: Chunyang
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiangfang
authors.initials: X
authors.lastname: Chen
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Liu
authors.forename: Yingying
authors.initials: Y
authors.lastname: Le
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005353:Fibronectins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D005353:Fibronectins; D016328:NF-kappa B; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D013267:Stilbenes; D019255:NADPH Oxidases; C515768:Cyba protein, rat; C060505:neutrophil cytosolic factor 1; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose; D000077185:Resveratrol