Impact of mitochondria reactive oxygen species in the pathogenesis of diabetic macro- and micro vascular complications.

我们以前提出，高血糖诱导的线粒体活性氧的过度生产是糖尿病并发症的发展中的一个关键事件。在2006-2007年期间，我们基于我们的假设进行了以下研究：本研究利用Tie 2启动子/增强子构建了一种在内皮细胞特异性表达MnSOD的转基因小鼠（eMnSOD-Tg），并在体内研究了线粒体活性氧产生对糖尿病视网膜病变的影响。使用免疫组织化学，MnSOD在内皮细胞中的过度表达被证实在eMnSOD-Tg小鼠。通过链脲佐菌素引入糖尿病，尿8-羟基脱氧鸟苷（线粒体氧化应激的标志物）水平以及视网膜中VEGF mRNA和蛋白质以及纤连蛋白mRNA的表达在野生型同窝仔中增加。然而，这些观察结果在eMnSOD-Tg小鼠中得到改善，尽管对照和eMnSOD-Tg小鼠显示出相当的高血糖水平。在本研究中，我们新开发了一系列转基因小鼠，它们在内皮细胞中特异性表达MnSOD。此外，血管内皮细胞特异性超氧化物歧化酶的过度表达可以预防体内糖尿病视网膜病变。

We previously proposed that hyperglycemia-induced mitochondrial ROS overproduction is a key event in the development of diabetic complications. During 2006-2007, we have performed below project based on our hypothesis.In this study, we established a novel transgenic mouse (eMnSOD-Tg), which specifically expressed MnSOD in endothelial cells, by employing a Tie2 promoter/enhancer, and investigated the impact of mitochondrial ROS production on diabetic retinopathy in vivo. Using immunohistochemistry, overexpression of MnSOD in endothelial cells was confirmed in eMnSOD-Tg mice. By introduction of diabetes by streptozotocin, levels of urinary 8-hydroxydeoxyguanosine, a marker of mitochondrial oxidative stress, and expression of VEGF mRNA and protein and fibronectin mRNA in retinas were increased in wild-type littermates. However, these observations were ameliorated in eMnSOD-Tg mice, although control and eMnSOD-Tg mice showed a comparable level of hyperglycemia. In the present study, we newly developed a line of transgenic mice, which specifically express MnSOD in endothelium. In addition, overexpression of mitochondrial-specific SOD in endothelium could prevent diabetic retinopathy in vivo.