A mechanistic study of resveratrol in improving diabetic nephropathy and deranged energy metabolism

• Main Authors: Kuan Hsing Chen, 陳冠興
• Other Authors: J. K. Chen
• Format: Others
• Published: 2011
• Online Access: http://ndltd.ncl.edu.tw/handle/71033579964110699940

博士 === 長庚大學 === 臨床醫學研究所 === 100 === Diabetes mellitus (DM) is a chronic metabolic disease associated with a wide range of complications affecting most organ systems. Diabetic nephropathy (DN) is the major cause of end-stage renal disease. The early changes in DN are characterized by an increase in kidney size, glomerular volume, and glomerular filtration, followed by the accumulation of glomerular extracellular matrix, increased urinary albumin excretion, glomerular sclerosis, and tubular fibrosis. Resveratrol (RSV) is a natural antioxidant with diverse biological effects, including modulation of immune function, anti-inflammation, anti-diabetes and cancer chemoprevention. The present study used male Sprague–Dawley rats injected with streptozotocin to induce type 1 diabetes to examine the beneficial effects of RSV on DN and explored the possible mechanism of RSV action. The DM rats were treated with or without RSV at 0.75 mg/kg body weight 3 times a day for 8 weeks. We showed that urinary albumin excretion, glomerular hypertrophy and expressions of fibronectin, collagen IV, and TGF-β in the glomeruli were all alleviated in RSV-treated DM rats, compared to the untreated DM rats. RSV inhibited phosphorylation of smad2, smad3 and ERK 1/2 in diabetic rat kidneys. In addition, RSV treatment reduced the thickness of the glomerular basement membrane to the original thickness and increased nephrin expressions to normal levels in DM rats. These findings suggested that RSV alleviates early glomerulosclerosis in DN through TGF-β/smad and ERK 1/2 inhibition. In addition, podocyte injuries of the diabetic kidneys are also lessened by RSV. Progression of early DN has been thought to be related to energy metabolic disorders. In the previous report, RSV has been demonstrated to ameliorate DN. However, the mechanisms underlying RSV effects on energy metabolism in diabetic rats are still unclear. In the present study, electrospray ionization-tandem mass spectrometry was employed to characterize the urine and plasma metabolomes of the control, streptozotocin-induced DM and RSV-treated DM rats. Based on principal component analysis and heat map analysis results, we showed that there were significant metabolomic differences between control and experimental groups. Treatment with RSV significantly reduced the metabolic abnormalities in DM rats. In comparison with the age-matched control rats, the level of carnitine was lower and the levels of acetylcarnitine and butyrylcarnitine were higher in the urine and plasma of DM rats. RSV treatment ameliorated the deranged carnitine metabolism in DM rats. In addition, RSV treatment attenuated the diabetic ketoacidosis and muscle protein degradation as evidenced from the attenuation of elevated urinary methyl-histidine and plasma branched-chain amino acids levels in DM rats. The beneficial effects of RSV were correlated with activation of hepatic AMP-activated protein kinase and SIRT1 expression, increase of hepatic and muscular mitochondrial biogenesis and inhibition of muscle NF-κB activities. This study concluded that RSV possesses multiple beneficial effects in insulin-deficient DM rats, particularly in improving energy metabolism and reducing protein wasting.