Inoguchi Toyoshi, Sonta Toshiyo, Tsubouchi Hirotaka, Etoh Takashi, Kakimoto Maiko, Sonoda Noriyuki, Sato Naoichi, Sekiguchi Naotaka, Kobayashi Kunihisa, Sumimoto Hideki, Utsumi Hideo, Nawata Hajime
Departments of Medicine and Bioregulatory Science and Molecular and Structure Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S227-32. doi: 10.1097/01.asn.0000077407.90309.65.
Hyperglycemia seems to be an important causative factor in the development of micro- and macrovascular complications in patients with diabetes. Several hypotheses have been proposed to explain the adverse effects of hyperglycemia on vascular cells. Both protein kinase C (PKC) activation and oxidative stress theories have increasingly received attention in recent years. This article shows a PKC-dependent increase in oxidative stress in diabetic vascular tissues. High glucose level stimulated reactive oxygen species (ROS) production via a PKC-dependent activation of NAD(P)H oxidase in cultured aortic endothelial cells, smooth muscle cells, and renal mesangial cells. In addition, expression of NAD(P)H oxidase components were shown to be upregulated in vascular tissues and kidney from animal models of diabetes. Furthermore, several agents that were expected to block the mechanism of a PKC-dependent activation of NAD(P)H oxidase clearly inhibited the increased oxidative stress in diabetic animals, as assessed by in vivo electron spin resonance method. Taken together, these findings strongly suggest that the PKC-dependent activation of NAD(P)H oxidase may be an essential mechanism responsible for increased oxidative stress in diabetes.
高血糖似乎是糖尿病患者微血管和大血管并发症发生发展的一个重要致病因素。人们提出了几种假说以解释高血糖对血管细胞的不良影响。近年来，蛋白激酶C（PKC）激活理论和氧化应激理论越来越受到关注。本文显示糖尿病血管组织中氧化应激的增加依赖于PKC。高糖水平通过PKC依赖性激活培养的主动脉内皮细胞、平滑肌细胞和肾系膜细胞中的NAD（P）H氧化酶，刺激活性氧（ROS）生成。此外，在糖尿病动物模型的血管组织和肾脏中，NAD（P）H氧化酶成分的表达被证明上调。此外，通过体内电子自旋共振方法评估，几种预期可阻断PKC依赖性激活NAD（P）H氧化酶机制的药物，明显抑制了糖尿病动物氧化应激的增加。综上所述，这些发现强烈表明，PKC依赖性激活NAD（P）H氧化酶可能是糖尿病中氧化应激增加的一个关键机制。
