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Chuangxin Huang, Joshua Wang, Sarah Zhang; Cigarette smoke and RPE injury: role of oxidative stress and ER stress. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3198.
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Cigarette smoking is a significant risk factor for age-related macular degeneration (AMD) characterized by injury and dysfunction of the retinal pigment epithelium (RPE) and photoreceptor cells. Recent evidence suggests that endoplasmic reticulum (ER) stress plays a fundamental role in regulation of cell survival and function. The aim of this study was to decipher the role of ER stress and its interaction with oxidative stress in cigarette smoke-induced RPE cell injury.
Cultured human RPE (ARPE-19) cells were exposed to cigarette smoking condensate extract (CSE) for up to 48 hrs. ER stress markers, signaling pathways of unfolded protein response, cell survival and apoptosis were examined at 6, 12, and 24 h. Oxidative stress was manipulated by anti-oxidants or overexpressing or downregulating Nrf2 gene, and ER stress was manipulated by chemical chaperones and UPR genes.
Expression of ER stress markers (e.g. p-eIF2α and GRP78), and pro-apoptotic UPR genes (such as CHOP) were significantly increased in CSE-treated cells in dose- and time-dependent manners. Pre-treatment of cells with anti-oxidant NAC or chemical chaperone TMAO markedly reduced CSE-induced ER stress and protected cells from CSE-induced apoptosis. Overexpressing Nrf2 showed similar protective effects. In contrast, downregulating of Nrf2 by siRNA sensitized RPE cells to CSE-induced ER stress-associated apoptotic pathways and exacerbated cell death.
These results indicate a close interaction between oxidative stress and ER stress in cigarette smoke-induced RPE cell damage. Future studies are needed to delineate the role and mechanism of ER stress-associated cellar pathways in modulating RPE cell activity and survival during normal and disease conditions such as AMD.
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