Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degeneration
Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degeneration
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DOI：
10.1111/j.1471-4159.2007.04839.x
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发表时间：
2007-11-01
影响因子：
4.7
通讯作者：
Campochiaro, Peter A.
中科院分区：
文献类型：
--
作者：
Dong, Aling;Shen, JiKui;Campochiaro, Peter A.
氧化损伤导致老年性黄斑变性或视网膜色素变性患者视网膜细胞死亡。一种治疗方法是识别和消除氧化损伤的来源。另一种方法是确定保护细胞免受多种氧化损伤来源的治疗方法。在这项研究中，我们研究了胶质细胞源性神经营养因子（GDNF）的表达增加在三种氧化损伤诱导的视网膜变性模型中的作用。双转基因小鼠与多西环素诱导的GDNF在视网膜中的表达暴露于百草枯，硫酸亚铁，或高氧，氧化损伤和视网膜细胞死亡的所有来源。与对照组相比，视网膜中GDNF表达增加的小鼠显示出通过视网膜电图测量的视网膜功能的显著保留，视网膜细胞层的变薄减少，并且TUNEL阳性细胞较少，表明视网膜细胞死亡较少。过表达GDNF的小鼠对丙烯醛、硝基酪氨酸和8-羟基脱氧鸟苷的染色也较少，表明对脂质、蛋白质和DNA的氧化损伤较少。这表明GDNF不仅在细胞凋亡开始前允许细胞耐受更高水平的氧化损伤，而且还减少了氧化应激对关键大分子的损伤。这些数据表明，GDNF的基因转移应被视为视网膜变性治疗的一个组成部分，其中氧化损伤起着重要作用。
Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO4, or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role.