Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice
Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice
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DOI：
10.1111/jnc.12116
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发表时间：
2013-04-01
影响因子：
4.7
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
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作者：
Nakanishi, Tomohiro;Shimazawa, Masamitsu;Hara, Hideaki
暴露于过量水平的光诱导感光细胞凋亡，并且可以是年龄相关性黄斑变性（AMD）的致病因素。然而，介导这种凋亡反应的细胞事件知之甚少。在这里，我们研究了内质网（ER）应激在小鼠视网膜和小鼠感光细胞（661 W）光诱导细胞死亡中的作用。过度的光暴露导致视网膜功能障碍、光感受器变性和细胞凋亡。此外，在光暴露的视网膜中，多泛素化蛋白的积累和ER应激相关因子的转录表达增加，包括78 kDa葡萄糖调节蛋白（GRP 78）/免疫球蛋白结合蛋白（BiP）和C/EBP同源蛋白（CHOP）。光暴露也诱导细胞死亡和上调的多聚泛素化蛋白，S-视蛋白聚集，bip和chop的mRNA在661 W细胞在体外。敲低chop mRNA可抑制光暴露诱导的感光细胞死亡。此外，治疗与BiP诱导剂X（BIX），ER应激抑制剂，诱导bip mRNA和减少CHOP的表达和光诱导的感光细胞死亡。这些数据表明，过度的ER应激可通过激活CHOP依赖性凋亡途径诱导光暴露视网膜中的感光细胞死亡，这表明ER应激可能在光暴露诱导的视网膜损伤中起关键作用。
Exposure to excessive levels of light induces photoreceptor apoptosis and can be a causative factor in age-related macular degeneration (AMD). However, the cellular events that mediate this apoptotic response are poorly understood. Here, we investigated the roles of endoplasmic reticulum (ER) stress in light-induced cell death in the murine retina and murine photoreceptor cells (661W). Excessive light exposure induced retinal dysfunction, photoreceptor degeneration, and apoptosis. Furthermore, the accumulation of polyubiquitinated proteins and the transcriptional expression of ER stress-related factors, including 78-kDa glucose-regulated protein (GRP78)/immunoglobulin-binding protein (BiP) and C/EBP-homologous protein (CHOP), were increased in light-exposed retinas. Light exposure also induced both cell death and up-regulation of polyubiquitinated proteins, S-opsin aggregation, bip and chop mRNAs in 661W cells in vitro. Knock-down of chop mRNA inhibited photoreceptor cell death induced by light exposure. Furthermore, treatment with BiP inducer X (BIX), an ER stress inhibitor, induced bip mRNA and reduced both chop expression and light-induced photoreceptor cell death. These data indicate that excessive ER stress may induce photoreceptor cell death in light-exposed retinas via activation of the CHOP-dependent apoptotic pathway, suggesting that the ER stress may play a pivotal role in light exposure-induced retinal damage.