A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat
A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat
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DOI：
10.2337/diabetes.52.2.506
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发表时间：
2003-02-01
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：
Asnaghi, V;Gerhardinger, C;Lorenzi, M
我们测试了这样的假设：在短期糖尿病后观察到的视网膜内神经元凋亡和神经胶质原纤维酸性蛋白（GFAP）表达增加是由多元醇途径活性介导的。链脲佐菌素诱导糖尿病 10 周且 GHb 水平为 16 +/- 2%（平均 SD）的大鼠显示，与非糖尿病大鼠相比，视网膜山梨醇和果糖水平升高，星形胶质细胞中 GFAP 免疫染色减弱，Muller 胶质细胞中出现显着的 GFAP 表达，并且凋亡神经元数量增加四倍。经历凋亡的细胞对醛糖还原酶具有免疫反应性。索宾尼尔是一种醛糖还原酶抑制剂，可以预防所有异常情况。强化胰岛素治疗也可以预防大多数异常，尽管 Glib 仅降低至 12 +/- 1%。与大鼠相比，糖尿病小鼠在其他组织中的醛糖还原酶活性要低得多，它们不会在视网膜中积累山梨醇和果糖，并且在 Glib 水平为 14 +/- 2% 的情况下，可以免受神经元凋亡和 GFAP 变化的影响。这项工作记录了视网膜中多元醇途径活性的离散细胞后果，并且表明该途径的激活和“视网膜神经病变”需要严重的高血糖和/或高活性的醛糖还原酶。这些发现对于如何评估多元醇途径在糖尿病视网膜病变中的作用具有重要意义。
We tested the hypothesis that the apoptosis of inner retina neurons and increased expression of glial fibrillary acidic protein (GFAP) observed in the rat after a short duration of diabetes are mediated by polyol pathway activity. Rats with 10 weeks of streptozotocin-induced diabetes and GHb levels of 16 +/- 2% (mean SD) showed increased retinal levels of sorbitol and fructose, attenuation of GFAP immunostaining in astrocytes, appearance of prominent GFAP expression in Muller glial cells, and a fourfold increase in the number of apoptotic neurons when compared with nondiabetic rats. The cells undergoing apoptosis were immunoreactive for aldose reductase. Sorbinil, an inhibitor of aldose reductase, prevented all abnormalities. Intensive insulin treatment also prevented most abnormalities, despite reducing Glib only to 12 +/- 1%. Diabetic mice, known to have much lower aldose reductase activity in other tissues when compared with rats, did not accumulate sorbitol and fructose in the retina and were protected from neuronal apoptosis and GFAP changes in the presence of Glib levels of 14 +/- 2%. This work documents discrete cellular consequences of polyol pathway activity in the retina, and it suggests that activation of the pathway and "retinal neuropathy" require severe hyperglycemia and/or high activity of aldose reductase. These findings have implications for how to evaluate the role of the polyol pathway in diabetic retinopathy.