Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage
Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage
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DOI：
10.1523/jneurosci.4866-04.2005
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发表时间：
2005-03
期刊：
影响因子：
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通讯作者：
M. Tanito;Yongwon Kwon;N. Kondo;J. Bai;H. Masutani;Hajime Nakamura;J. Fujii;A. Ohira;J. Yodoi
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文献类型：
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作者：
M. Tanito;Yongwon Kwon;N. Kondo;J. Bai;H. Masutani;Hajime Nakamura;J. Fujii;A. Ohira;J. Yodoi
过度光照会导致视网膜光感受器细胞损伤，导致各种视网膜疾病的发生和发展。我们测试了香叶基香叶内酮(GGA)，一种非环多异戊二烯类化合物，对光诱导的小鼠视网膜损伤的影响。口服GGA(1.0 mg/d)5d，可诱导视网膜色素上皮(RPE)表达硫氧还蛋白(TRX)和热休克蛋白72(HSP72)。白光照射(8000lux，2 h)后，GGA组与生理盐水组相比，24 h和96 h的UTP缺口末端标记阳性的光感受器细胞百分率显著降低，96 h的光感受器细胞核数目和a波和b波的视网膜电波幅显著增加。GGA可抑制氧化应激标志物8-羟基-2-脱氧鸟苷和4-羟基-2-壬醛修饰蛋白的光诱导表达上调。为了阐明GGA和TRX的细胞保护机制，我们使用了人的K-1034 RPE细胞和小鼠光感受器来源的661W细胞。在K-1034细胞中，GGA(10μm)可诱导细胞内Trx、HSP72和胞外Trx，但不能诱导胞外HSP72。胞外Trx(0.75 nm)可减轻H_2O_2(200μm)对661W细胞的损伤作用。GGA预处理和Trx在K-1034细胞中的过表达可拮抗H_2O_2(50μm)对细胞胶乳微珠掺入的抑制作用。通过诱导TRX和可能的HSP72来保护RPE细胞的吞噬活性，以及通过释放TRX来消除RPE细胞光感受器层的氧化应激，这可能是GGA介导的细胞保护机制。因此，Trx是一种从RPE细胞释放的神经营养因子，在维持光感受器细胞完整性方面起着至关重要的作用。
Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 μm) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nm) attenuated H2O2 (200 μm)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H2O2 (50 μm)-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.