Contribution of polyol pathway to diabetes-induced oxidative stress
Contribution of polyol pathway to diabetes-induced oxidative stress
复制标题
DOI：
10.1097/01.asn.0000077408.15865.06
复制
发表时间：
2003-08-01
影响因子：
13.6
通讯作者：
Chung, SK
中科院分区：
文献类型：
--
作者：
Chung, SSM;Ho, ECM;Chung, SK
糖尿病引起氧化应激增加，其被认为在各种糖尿病并发症的发病机制中起重要作用。然而，高血糖诱导的氧化应激的来源尚不清楚。发现多元醇途径是糖尿病小鼠晶状体和神经中氧化应激的主要贡献者。该途径中的第一种酶，醛糖还原酶（AR），将葡萄糖还原为山梨醇，然后通过山梨醇脱氢酶（SDH）将其转化为果糖。在晶状体中特异性过表达AR的转基因小鼠在高血糖时表现出氧化应激显著增加，如晶状体中GSH减少和丙二醛增加所示。将SDH缺陷突变引入这些转基因小鼠中显著地使GSH和丙二醛水平正常化。这些结果表明，这两种酶的多元醇途径有助于高血糖症诱导的氧化应激的透镜。在野生型小鼠中，糖尿病导致其坐骨神经中GSH的显着减少，表明氧化应激。在AR无效突变小鼠中，糖尿病并没有导致神经GSH水平的任何下降。这些结果表明，类似于透镜中的情况，AR也是高血糖诱导的神经氧化应激的主要贡献者。虽然通过多元醇途径的葡萄糖流量增加导致晶状体和神经中的糖尿病病变，但机制可能不同。AR诱导的渗透应激可能是糖尿病性白内障的原因，而AR诱导的氧化应激可能是神经元功能障碍的原因。
Diabetes causes increased oxidative stress, which is thought to play an important role in the pathogenesis of various diabetic complications. However, the source of the hyperglycemia-induced oxidative stress is not clear. It was found that the polyol pathway is the major contributor to oxidative stress in the lenses and nerves of diabetic mice. The first enzyme in the pathway, aldose reductase (AR), reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SDH). Transgenic mice that overexpress AR specifically in their lenses showed a significant increase in oxidative stress when they became hyperglycemic, as indicated by a decrease in GSH and an increase in malondialdehyde in their lenses. Introducing an SDH-deficient mutation into these transgenic mice significantly normalized the GSH and malondialdehyde levels. These results indicate that both enzymes of the polyol pathway contributed to hyperglycemia-induced oxidative stress in the lens. In the wild-type mice, diabetes caused a significant decrease in GSH in their sciatic nerves, indicative of oxidative stress. In the AR null mutant mice, diabetes did not lead to any decrease in the nerve GSH level. These results indicate that similar to the situation in the lens, AR is also the major contributor to hyperglycemia-induced oxidative stress in the nerve. Although increased flux of glucose through the polyol pathway leads to diabetic lesions in both the lenses and nerve, the mechanisms may be different. AR-induced osmotic stress seems to be the cause of diabetic cataract, whereas AR-induced oxidative stress is probably the cause of neuronal dysfunction.