Wen Donghai, Huang Xinzhong, Zhang Min, Zhang Liying, Chen Jing, Gu Yong, Hao Chuan-Ming
Department of Internal Medicine, Huashan Hospital, Fudan University, Shanghai, China.
PLoS One. 2013 Dec 3;8(12):e82336. doi: 10.1371/journal.pone.0082336. eCollection 2013.
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.
血管生成在糖尿病肾病（DN）的发病机制中起重要作用。在本研究中，我们调查了白藜芦醇（一种具有抗血管生成活性的多酚）对DN的治疗潜力。在1型糖尿病大鼠模型中，白藜芦醇治疗抑制了尿白蛋白排泄、肾脏重量和肌酐清除率的增加。白藜芦醇治疗还降低了糖尿病大鼠肾小球直径、系膜积聚、肾小球基底膜厚度和肾纤维化的增加。在糖尿病肾脏中，观察到血管内皮生长因子（VEGF）、Flk-1和血管生成素2的表达增加，而Tie-2的表达降低。白藜芦醇治疗减弱了这些血管生成激素及其相关受体的变化。在每组大鼠中未检测到血管生成素1表达的变化。白藜芦醇还分别显著下调了高糖诱导的培养小鼠肾小球足细胞和内皮细胞中VEGF和Flk-1的表达。敲低沉默信息调节因子1（Sirt1）的表达减弱了这些作用。相反，在培养的内皮细胞中上调Sirt1可降低Flk-1的表达。白藜芦醇预处理还抑制了由VEGF引起的培养内皮细胞通透性增加和细胞连接破坏。综上所述，本研究表明白藜芦醇可能通过调节血管生成来减轻DN。
