Koya Daisuke, Hayashi Kazuyuki, Kitada Munehiro, Kashiwagi Atsunori, Kikkawa Ryuichi, Haneda Masakazu
Department of Medicine, Shiga University of Medical Science, Shiga, Japan.
J Am Soc Nephrol. 2003 Aug;14(8 Suppl 3):S250-3. doi: 10.1097/01.asn.0000077412.07578.44.
Numerous reports have demonstrated that oxidative stress induced by diabetes plays an important role in the development and progression of diabetic vascular complications including nephropathy. Indeed, there is emerging evidence that the formation of reactive oxygen species (ROS) is a direct consequence of hyperglycemia. Biomarkers for oxidative damage to DNA, lipids, and proteins are also supporting the concept of increased oxidative stress in diabetes and diabetic nephropathy. However, there is an unanswered question: When does oxidative stress as a pathogenetic event occur in the process of diabetic nephropathy? To answer this question, glomerular ROS was imaged with the use of 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The image of DCF fluorescence was strong in glomeruli from diabetic rats as compared with that of glomeruli from nondiabetic control rats. mRNA expression of antioxidant enzymes such as catalase, glutathione peroxidase, Cu/Zn superoxide dismutase, and heme oxygenase-1 (HO-1) was also determined because oxidative stress definitely refers to the situation of an imbalance between the production of ROS and antioxidant defense. The mRNA expression of catalase, glutathione peroxidase, and Cu/Zn superoxide dismutase 2 wk after the induction of diabetes was not significantly different from that in control rats. Alternatively, mRNA and protein expression of HO-1 was strongly induced by 16-fold in diabetic glomeruli after the induction of diabetes. Antioxidant treatment with either vitamin E or probucol almost completely normalized HO-1 overexpression in diabetic glomeruli, supporting the existence of oxidative stress in the glomeruli of early diabetes. Furthermore, It has reported that antioxidant treatment with vitamin E, probucol, alpha-lipoic acid, or taurine normalized diabetes-induced not only renal dysfunction such as albuminuria and glomerular hypertension but also glomerular pathologies. In summary, oxidative stress by diabetes could play a crucial role in the development and progression of diabetic nephropathy, and antioxidant treatment could be a potential therapeutic procedure for diabetic nephropathy.
大量报告表明，糖尿病诱导的氧化应激在包括肾病在内的糖尿病血管并发症的发生和发展中起重要作用。事实上，越来越多的证据表明活性氧（ROS）的形成是高血糖的直接后果。DNA、脂质和蛋白质氧化损伤的生物标志物也支持糖尿病和糖尿病肾病中氧化应激增加的概念。然而，有一个问题尚未得到解答：在糖尿病肾病过程中，氧化应激作为致病事件何时发生？为了回答这个问题，使用2',7'-二氯荧光素二乙酸酯（DCFH-DA）对肾小球ROS进行成像。与非糖尿病对照大鼠的肾小球相比，糖尿病大鼠肾小球中的DCF荧光图像更强。还测定了过氧化氢酶、谷胱甘肽过氧化物酶、铜/锌超氧化物歧化酶和血红素加氧酶-1（HO-1）等抗氧化酶的mRNA表达，因为氧化应激肯定是指ROS产生与抗氧化防御之间失衡的情况。糖尿病诱导2周后，过氧化氢酶、谷胱甘肽过氧化物酶和铜/锌超氧化物歧化酶的mRNA表达与对照大鼠无显著差异。相反，糖尿病诱导后，糖尿病肾小球中HO-1的mRNA和蛋白表达强烈诱导增加了16倍。用维生素E或普罗布考进行抗氧化治疗几乎完全使糖尿病肾小球中HO-1的过表达恢复正常，支持早期糖尿病肾小球中存在氧化应激。此外，据报道，用维生素E、普罗布考、α-硫辛酸或牛磺酸进行抗氧化治疗不仅使糖尿病诱导的肾功能障碍如蛋白尿和肾小球高血压恢复正常，而且使肾小球病变恢复正常。总之，糖尿病引起的氧化应激可能在糖尿病肾病的发生和发展中起关键作用，抗氧化治疗可能是糖尿病肾病的一种潜在治疗方法。
