Amano Shinjiro, Yamagishi Sho ichi, Kato Noriaki, Inagaki Yosuke, Okamoto Tamami, Makino Mitsuhiro, Taniko Kaori, Hirooka Hiroko, Jomori Takahito, Takeuchi Masayoshi
Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, 830-0011, Kurume, Japan.
Biochem Biophys Res Commun. 2002 Nov 29;299(2):183-8. doi: 10.1016/s0006-291x(02)02584-6.
The polyol pathway consists of two enzymes, aldose reductase (AR) and sorbitol dehydrogenase (SDH). There is a growing body of evidence to suggest that acceleration of the polyol pathway is implicated in the pathogenesis of diabetic vascular complications. However, a functional role remains to be elucidated for SDH in the development and progression of diabetic retinopathy. In this study, cultured bovine retinal capillary pericytes were used to investigate the effects of SDH overexpression on glucose toxicity. High glucose modestly increased reactive oxygen species (ROS) generation, decreased DNA synthesis, and up-regulated vascular endothelial growth factor (VEGF) mRNA levels in cultured pericytes. SDH overexpression was found to significantly stimulate ROS generation in high glucose-exposed pericytes and subsequently potentiate the cytopathic effects of glucose. Fidarestat, a newly developed AR inhibitor, and N-acetylcysteine, an antioxidant, completely prevented these deleterious effects of SDH overexpression on pericytes. Furthermore, fidarestat administration was found to significantly prevent vascular hyperpermeability, the characteristic changes of the early phase of diabetic retinopathy, in streptozotocin-induced diabetic rats. Our present results suggest that SDH-mediated conversion of sorbitol to fructose and the resultant ROS generation may play an active role in the pathogenesis of diabetic retinopathy. Blockage of sorbitol formation by fidarestat could be a promising therapeutic strategy for the treatment of early phase of diabetic retinopathy.
多元醇途径由两种酶组成，即醛糖还原酶（AR）和山梨醇脱氢酶（SDH）。越来越多的证据表明，多元醇途径的加速与糖尿病血管并发症的发病机制有关。然而，SDH在糖尿病视网膜病变发生和发展中的功能作用仍有待阐明。在本研究中，使用培养的牛视网膜毛细血管周细胞来研究SDH过表达对葡萄糖毒性的影响。高糖适度增加了培养的周细胞中活性氧（ROS）的产生，降低了DNA合成，并上调了血管内皮生长因子（VEGF）的mRNA水平。发现SDH过表达能显著刺激高糖处理的周细胞中ROS的产生，并随后增强葡萄糖的细胞病变作用。新型AR抑制剂非达司他和抗氧化剂N-乙酰半胱氨酸完全阻止了SDH过表达对周细胞的这些有害影响。此外，发现给予非达司他能显著预防链脲佐菌素诱导的糖尿病大鼠的血管高通透性，这是糖尿病视网膜病变早期的特征性变化。我们目前的结果表明，SDH介导的山梨醇向果糖的转化以及由此产生的ROS生成可能在糖尿病视网膜病变的发病机制中起积极作用。非达司他阻断山梨醇形成可能是治疗糖尿病视网膜病变早期的一种有前景的治疗策略。
