Chung Stephen S M, Ho Eric C M, Lam Karen S L, Chung Sookja K
Institute of Molecular Biology, Department of Medicine, The University of Hong Kong, Hong Long, China.
J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S233-6. doi: 10.1097/01.asn.0000077408.15865.06.
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.
糖尿病会导致氧化应激增加，氧化应激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。研究发现，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促成因素。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的转基因小鼠在血糖升高时氧化应激显著增加，这表现为其晶状体中谷胱甘肽（GSH）减少和丙二醛增加。将SDH缺陷突变引入这些转基因小鼠可显著使GSH和丙二醛水平正常化。这些结果表明，多元醇途径的两种酶都促成了晶状体中高血糖诱导的氧化应激。在野生型小鼠中，糖尿病导致其坐骨神经中的GSH显著降低，这表明存在氧化应激。在AR基因敲除突变小鼠中，糖尿病并未导致神经GSH水平下降。这些结果表明，与晶状体中的情况类似，AR也是神经中高血糖诱导的氧化应激的主要促成因素。尽管通过多元醇途径的葡萄糖通量增加会导致晶状体和神经中的糖尿病病变，但机制可能不同。AR诱导的渗透压似乎是糖尿病性白内障的病因，而AR诱导的氧化应激可能是神经元功能障碍的病因。
