Nicolas M G, Fujiki K, Murayama K, Suzuki M T, Shindo N, Hotta Y, Iwata F, Fujimura T, Yoshikawa Y, Cho F, Kanai A
Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan.
Exp Eye Res. 1996 Apr;62(4):399-408. doi: 10.1006/exer.1996.0045.
Initial investigations done in this laboratory detected increased albumin and decreased glyceraldehyde 3-phosphate dehydrogenase concentrations in the retina of an animal model manifesting early onset macular degeneration. Both glyceraldehyde 3-phosphate dehydrogenase and albumin are markers of oxidative stress in cells. In this study, we used the same animal model to study further biochemical and physiological processes which may be involved in the pathogenesis of early onset macular degeneration in monkeys. We detected 60% lower catalase and glutathione peroxidase activities in the affected retinas suggesting lower antioxidant activities and oxidative stress. One of the consequences of oxidative stress is the production of metallothionein, a low molecular weight protein also induced by high concentrations of heavy metals such as zinc. Metallothionein was detected by RT-PCR in these monkey retinas. However initial quantitative PCR studies on this protein showed that the synthesis of metallothionein in affected retinas appears to be less than in normal controls. The affected retinas also showed a fourfold lower zinc concentration compared with the normal controls. No significant difference, however, could be detected in the zinc concentrations in plasma samples. Since induction of metallothionein synthesis is mediated by transcription factors which require heavy metals such as zinc for binding to specific sites in the DNA, the lowered zinc concentration may, thus, correlate with the lowered metallothionein expression. And since metallothionein is suggested to function as a free radical scavenger, the lowered metallothionein synthesis may consequently contribute to increased peroxidation reactions in the affected retinas. It appears therefore, that oxidative stress and the decreased metallothionein synthesis may be involved in the pathogenesis of early onset macular degeneration in this animal model.
该实验室进行的初步研究检测到，在表现出早发性黄斑变性的动物模型的视网膜中，白蛋白增加而甘油醛-3-磷酸脱氢酶浓度降低。甘油醛-3-磷酸脱氢酶和白蛋白都是细胞氧化应激的标志物。在本研究中，我们使用相同的动物模型进一步研究可能参与猴子早发性黄斑变性发病机制的生化和生理过程。我们检测到受影响视网膜中的过氧化氢酶和谷胱甘肽过氧化物酶活性降低了60%，这表明抗氧化活性和氧化应激较低。氧化应激的后果之一是金属硫蛋白的产生，金属硫蛋白是一种低分子量蛋白质，高浓度的重金属如锌也可诱导其产生。通过RT-PCR在这些猴子视网膜中检测到了金属硫蛋白。然而，对该蛋白进行的初步定量PCR研究表明，受影响视网膜中金属硫蛋白的合成似乎低于正常对照组。与正常对照组相比，受影响视网膜中的锌浓度也降低了四倍。然而，血浆样本中的锌浓度未检测到显著差异。由于金属硫蛋白合成的诱导是由转录因子介导的，这些转录因子需要锌等重金属才能与DNA中的特定位点结合，因此锌浓度降低可能与金属硫蛋白表达降低相关。而且由于金属硫蛋白被认为具有自由基清除剂的功能，因此金属硫蛋白合成降低可能会导致受影响视网膜中的过氧化反应增加。因此，氧化应激和金属硫蛋白合成降低似乎可能参与了该动物模型中早发性黄斑变性的发病机制。
