Synergistic effect of osmotic and oxidative stress in slow-developing cataract formation
Synergistic effect of osmotic and oxidative stress in slow-developing cataract formation
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DOI：
10.1016/j.exer.2008.08.001
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发表时间：
2008-11-01
影响因子：
3.4
通讯作者：
Chung, Stephen S. M.
中科院分区：
文献类型：
--
作者：
Chan, Alfred W. H.;Ho, Ye-shih;Chung, Stephen S. M.
糖尿病是白内障发展的主要因素。在动物模型中，白内障在糖尿病的几天或几周内发展，已经确定山梨醇积累引起的渗透压导致白内障发展。这种机制可能解释了在不受控制的持续高血糖患者中有时发现的罕见急性白内障病例，但不能解释多年糖尿病后发生的绝大多数白内障。因此，需要一种能够模拟糖尿病缓慢发展的白内障的模型。本研究以山梨醇脱氢酶（SDH）缺陷小鼠为模型，观察了渗透压和氧化应激在糖尿病患者白内障发生中的作用。通过HPLC测量山梨醇和观察SDH缺陷小鼠中醛糖还原酶（AR）无效突变阻断山梨醇蓄积的作用，评估渗透压应激的作用。通过观察维生素E治疗的效果和谷胱甘肽过氧化物酶-1（Gpx-1）无效突变对这些小鼠白内障发展的影响来评估氧化应激的贡献。在SDH缺陷小鼠中，豆状核山梨醇水平显著增加，并且通过AR无效突变阻断山梨醇积累防止了白内障的发展，证明了渗透应激在白内障发展中的作用。SDH缺乏不影响透镜氧化应激状态。然而，维生素E治疗显著降低了白内障的发病率，Gpx-1缺乏加剧了这些小鼠的白内障发展。我们的研究结果表明，慢性氧化应激损害了透镜的晶状体调节机制。直到透镜山梨醇的适度增加增加了其晶状体调节功能的需求，这一点才变得明显。这种视网膜调节功能障碍模型得到以下事实的支持：在SDH缺陷小鼠的白内障前晶状体中，Na+/K+-ATP酶（细胞离子和水平衡的关键调节剂）的活性显著降低，并且维生素E治疗防止了Na+/K+-ATP酶活性的丧失。这种调节功能障碍模型可能解释了为什么血糖控制良好的糖尿病患者仍然容易发生白内障。(c)2008爱思唯尔有限公司保留所有权利。
Diabetes is a major contributing factor in cataract development. In animal models where cataracts develop within days or weeks of diabetes it is well established that osmotic stress from the accumulation of sorbitol leads to cataract development. This mechanism might explain the rare cases of acute cataract sometimes found in patients with uncontrolled sustained hyperglycemia but cannot account for the vast majority of cataracts that developed after years of diabetes. Thus, a model that can simulate diabetic slow-developing cataract is needed. The contribution of osmotic and oxidative stress in cataract development in sorbitol dehydrogenase (SDH) deficient mice, a model for slow-developing cataract in diabetic patients was determined. Contribution of osmotic stress was assessed by HPLC measurement of sorbitol and by observing the effect of blocking sorbitol accumulation by aldose reductase (AR) null mutation in the SDH deficient mice. Contribution of oxidative stress was assessed by observing the effect of vitamin E treatment and the effect of null mutation of glutathione peroxidase-1 (Gpx-1) on cataract development in these mice. Lenticular sorbitol level was significantly increased in the SDH deficient mice, and blocking sorbitol accumulation by the AR null mutation prevented cataract development, demonstrating the contribution of osmotic stress in cataract development. SDH deficiency did not affect lens oxidative stress status. However, treatment with vitamin E significantly reduced the incidence of cataract, and Gpx-1 deficiency exacerbated cataract development in these mice. Our findings suggest that chronic oxidative stress impaired the osmoregulatory mechanism of the lens. This was not evident until modest increases in lens sorbitol increased the demand of its osmoregulatory function. This osmoregulatory dysfunction model is supported by the fact that the activity of Na+/K+-ATPase, the key regulator of cellular ions and water balance, was dramatically reduced in the precataractous lenses of the SDH deficient mice, and that treatment with vitamin E prevented the loss of Na+/K+-ATPase activity. This osmoregulatory dysfunction model might explain why diabetic patients who control their blood glucose moderately well are still susceptible to develop cataract. (c) 2008 Elsevier Ltd. All rights reserved.