Abstract
Age-related macular degeneration (AMD) is characterized by the progressive degradation of photoreceptors and retinal pigment epithelium (RPE) cells. ARPE-19 is an RPE cell line established as an in vitro model for the study of AMD pathogenesis. Oxidative stress is an AMD pathogenesis factor that induces DNA damage. Thus, the oxidative stress-mediated DNA damage response (DDR) of ARPE-19 cells can be important in AMD pathogenesis. The metabolism of retinoids—which regulates cell proliferation, differentiation, and the visual cycle in the retina—was reported to be disturbed in AMD patients. In the present work, we studied the effect of all-trans retinoic acid (ATRA, a retinoid) on DDR in ARPE-19 cells subjected to oxidative stress. We observed that ATRA increased the level of reactive oxygen species (ROS), alkali-labile sites in DNA, DNA single-strand breaks, and cell death evoked by oxidative stress. ATRA did not modulate DNA repair or the distribution of cells in cell cycle in the response of ARPE-19 cells to oxidative stress. ATRA induced autophagy in the absence of oxidative stress, but had no effect on this process in the stress. ATRA induced over-expression of proliferation marker MKI67 and neovascularization marker VEGF-A. In conclusion, ATRA increased oxidative stress in ARPE-19 cells, resulting in more lesions to their DNA and cell death. Moreover, ATRA can modulate some properties of these cells, including neovascularization, which is associated with the exudative form of AMD. Therefore, ATRA can be important in the prevention, diagnosis, and therapy of AMD.
Highlights
Age-related macular degeneration (AMD) is a disease in which specialized neurons undergo cell death in the central part of the retina—the macula—leading to the complete loss of central vision
AMD is classified into two subgroups, (I) atrophic AMD, in which cells degenerate in the macular area; and (II) exudative AMD, resulting from choroidal neovascularization mediated by vascular endothelial growth factor A (VEGF-A) [2]
Since ARPE-19 cells were treated with an oxidant, we checked whether All-trans retinoic acid (ATRA) could modulate the level of intracellular reactive oxygen species (ROS) in oxidative stress
Summary
Age-related macular degeneration (AMD) is a disease in which specialized neurons (photoreceptors) undergo cell death in the central part of the retina—the macula—leading to the complete loss of central vision. Oxidative stress in the retina results from high consumption of oxygen, exposure to blue and UV lights and the phagocytic functions of RPE cells [3,4,5,6]. RPE cells are exposed to reactive oxygen species (ROS), and ROS-induced damage is frequently observed in AMD patients [7]. Impairments in the cellular antioxidant system, including lower activity of sodium dismutase (SOD) and glutathione peroxidase (GPx)—which were observed in AMD—can lead to ROS-induced DNA damage [9]. Aside from antioxidant enzymes and low molecular weight antioxidants (which neutralize ROS) the DNA damage response (DDR) can overcome the consequences of oxidative stress-induced DNA lesions. Others showed that post-mortem AMD retinas had a significantly higher number of apoptotic cells than normal retinas, indicating that DDR can be impaired in AMD [11]
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