Abstract
Angiogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with antiangiogenic activity in DN. In a type 1 diabetic rat model, resveratrol treatment blunted the increases of urine albumin excretion, kidney weight and creatinine clearance rate. The increases of glomerular diameter, mesangium accumulation, glomerular basement membrane thickness and renal fibrosis in diabetic rats were also reduced by resveratrol treatment. In the diabetic kidney, increased expression of vascular endothelial growth factor (VEGF), Flk-1 and angiopoietin 2, and reduced expression of Tie-2 were observed. These changes in angiogenic hormones and associated receptors were attenuated by resveratrol treatment. No changes in angiopoietin 1 expression were detected among each group of rats. Resveratrol also significantly downregulated high glucose-induced VEGF and Flk-1 expressions in cultured mouse glomerular podocytes and endothelial cells, respectively. These effects were attenuated by knocking-down silent information regulator 1 (Sirt1) expression. In contrast, upregulation of Sirt1 in cultured endothelial cells reduced Flk-1 expression. Increased permeability and cellular junction disruption of cultured endothelial cells caused by VEGF were also inhibited by resveratrol pretreatment. Taken together, the present study demonstrated that resveratrol may attenuate DN via modulating angiogenesis.
Highlights
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States, and affects approximately 40% of diabetic patients [1]
The urinary albumin excretion rate (UAER) was markedly elevated in the diabetic rats, while treatment with resveratrol significantly decreased the UAER after 8 weeks of treatment (Figure 1.C, CON 1.53±0.38mg/24h; DN 13.81±1.25mg/24h; DN+RSV 6.55±0.57mg/24h)
It has been suggested that the abnormal angiogenesis in DN, which is mostly mediated by vascular endothelial growth factor (VEGF)-Flk-1 system, is associated with increased permeability in the glomerular endothelial cells and leakage of plasma albumin into the urine, which further results in albuminuria and development and progression of DN [6]
Summary
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States, and affects approximately 40% of diabetic patients [1]. The main treatments for DN are glycemic, lipid and blood pressure control, plus reninangiotensin-aldosterone system (RAAS) blockade, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) [3]. There are still a great number of DN patients progressing into ESRD, even after the aggressive uses of these treatments [3,4]. The involvement of various factors such as hyperglycemia, angiotensin II, advanced glycation end products (AGEs), oxidative stress, transforming growth factor β (TGF-β), plasminogen activator inhibitor 1 (PAI-1), and connective tissue growth factor (CTGF) in DN has been reported [5]
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