Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy
Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy
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DOI：
10.2337/diabetes.53.9.2404
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发表时间：
2004-09-01
期刊：
影响因子：
7.7
通讯作者：
Lorenzi, M
中科院分区：
文献类型：
--
作者：
Dagher, Z;Park, YS;Lorenzi, M
当细胞内葡萄糖浓度高时，葡萄糖代谢的多元醇（山梨醇）途径在许多细胞类型中被激活，并且它可以通过几种机制产生细胞应激。多元醇通路在糖尿病视网膜病变发病机制中的作用仍然不确定，部分原因是它优先在半乳糖诱导的视网膜病变中进行了检查，部分原因是抑制研究可能尚未完全阻断该通路。已经观察到链脲佐菌素诱导的糖尿病大鼠准确地模拟了人类糖尿病视网膜病变的许多细胞过程特征，我们在糖尿病大鼠中测试了是否记录了多元醇途径的抑制防止了也存在于人类糖尿病中的一系列视网膜血管异常。醛糖还原酶的抑制剂，限速酶的途径，防止早期激活的补体在视网膜血管壁和补体抑制剂在糖尿病大鼠的水平下降，以及后来的血管周细胞和内皮细胞的凋亡和无细胞毛细血管的发展。大鼠和人视网膜内皮细胞均表现出醛糖还原酶免疫反应性，在器官培养中暴露于高葡萄糖的人视网膜增加了山梨醇的产生，其程度与在大鼠中观察到的相似。过量的醛糖还原酶活性可能是人类糖尿病视网膜病变的机制。
The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy.