Division of Endocrinology, Department of Internal Medicine, The First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, Zhengzhou 450052, People's Republic of China.
Mol Biol Rep. 2012 Sep;39(9):9085-93. doi: 10.1007/s11033-012-1780-z. Epub 2012 Jun 26.
Reactive oxygen species production has recently been established as an essential contributor in the development of diabetic nephropathy (DN). Resveratrol, a natural anti-oxidants with biological activity, is known to be an activator of sirtuin1 (Sirt1). Forkhead transcription factor O1 (FoxO1) plays a role not only in regulating metabolism but also in oxidant stress. The present study was carried out to examine whether resveratrol had protective effect on diabetic kidney by modulation of the Sirt1/FoxO1 pathway. To investigate the effect of FoxO1 on oxidant stress, male Sprague-Dawley rats were injected with a single dose of 60 mg/kg streptozotocin (STZ) to induce diabetes. Here we show that the FoxO1 activity was significantly reduced and with a concomitant decrease in the expression of FoxO1 target gene, catalase in diabetic kidney. The FoxO1 downregulation correlated with an increase in the generation of malondialdehyde (MDA), a decrease in the activity of SOD and an increase in the expression of collagen IV and fibronectin proteins in renal cortex of diabetic rats. Treatment with the sirtuin agonist resveratrol, with an increase in the expression of Sirt1, significantly increased FoxO1 activity in diabetic kidney. This correlated with a decrease in the generation of MDA, an increase in the activity of SOD, a partial reversal of collagen IV and fibronectin proteins levels and more improved kidney pathological and biochemical indicators changes. Together these results indicate that it is characterized by decreased activity of FoxO1 in diabetic kidney. These data also suggest that modulation of the Sirt1/FoxO1 pathway may be a potentially useful therapeutic target for DN.
活性氧物种的产生最近被确立为糖尿病肾病 (DN) 发展的一个重要贡献者。白藜芦醇是一种具有生物活性的天然抗氧化剂，已知是 Sirtuin1 (Sirt1) 的激活剂。叉头转录因子 O1 (FoxO1) 不仅在调节代谢中起作用，而且在氧化应激中也起作用。本研究旨在通过调节 Sirt1/FoxO1 通路来研究白藜芦醇是否对糖尿病肾脏具有保护作用。为了研究 FoxO1 对氧化应激的影响，雄性 Sprague-Dawley 大鼠单次注射 60mg/kg 链脲佐菌素 (STZ) 诱导糖尿病。在这里，我们表明 FoxO1 的活性显著降低，同时 FoxO1 靶基因过氧化氢酶的表达也降低，糖尿病肾脏中。FoxO1 的下调与丙二醛 (MDA) 的产生增加、SOD 活性降低以及糖尿病大鼠肾皮质中胶原蛋白 IV 和纤维连接蛋白蛋白表达增加有关。用 Sirtuin 激动剂白藜芦醇治疗可增加 Sirt1 的表达，显著增加糖尿病肾脏中的 FoxO1 活性。这与 MDA 的生成减少、SOD 活性增加、胶原蛋白 IV 和纤维连接蛋白蛋白水平部分逆转以及肾脏病理和生化指标变化的改善有关。这些结果表明，糖尿病肾脏中 FoxO1 的活性降低。这些数据还表明，调节 Sirt1/FoxO1 通路可能是治疗糖尿病肾病的一个潜在有用的治疗靶点。
