title: Resveratrol ameliorates early diabetic nephropathy associated with suppression of augmented TGF-β/smad and ERK1/2 signaling in streptozotocin-induced diabetic rats.
abstract: Diabetic nephropathy (DN) is the major cause of end-stage renal disease. The early changes in DN are characterized by an increased in kidney size, glomerular volume, and kidney function, followed by the accumulation of glomerular extracellular matrix, increased urinary albumin excretion (UAE), glomerular sclerosis, and tubular fibrosis. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in streptozotocin-induced diabetic rats. In the present study, we examined the beneficial effects of RSV on DN and explored the possible mechanism of RSV action. Male Sprague-Dawley rats were injected with streptozotocin at 65mg/kg body weight. The induction of diabetes mellitus (DM) was confirmed by a fasting plasma glucose level ≥300mg/dL and symptoms of polyphagia and polydipsia. The DM rats were treated with or without RSV at 0.75mg/kg body weight 3 times a day for 8 weeks. Animals were sacrificed and kidney histology was examined by microscopy. Urinary albumin excretion, glomerular hypertrophy and expressions of fibronectin, collagen IV, and TGF-β in the glomeruli were alleviated in RSV-treated DM rats, but not in untreated DM rats. In addition, RSV treatment reduced the thickness of the glomerular basement membrane (GBM) to the original thickness and increased nephrin expressions to normal levels in DM rats. Moreover, RSV inhibited phosphorylation of smad2, smad3 and ERK1/2 in diabetic rat kidneys. This is the first report showing that RSV alleviates early glomerulosclerosis in DN through TGF-β/smad and ERK1/2 inhibition. In addition, podocyte injuries of diabetic kidneys are lessened by RSV.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Kuan-Hsing
authors.initials: KH
authors.lastname: Chen
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Hung
authors.forename: Hsiang-Hao
authors.initials: HH
authors.lastname: Hsu
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Jing
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Yang
authors.forename: Jan-Kan
authors.initials: JK
authors.lastname: Chen
mesh_terms: D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D013267:Stilbenes / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D007004:Hypoglycemic Agents; D008565:Membrane Proteins; D051785:Smad Proteins; D013267:Stilbenes; D016212:Transforming Growth Factor beta; C113267:nephrin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol