All-Trans Retinoic Acid Modulates DNA Damage Response and the Expression of the VEGF-A and MKI67 Genes in ARPE-19 Cells Subjected to Oxidative Stress

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.

APR3 modulates oxidative stress and mitochondrial function in ARPE‐19 cells

“…However, increasing evidence indicated that overdose of ATRA supplement has deleterious effects on RPE cells. ATRA was found to increase ROS levels and oxidative stress-induced DNA damage in RPE cells (44). Chang et al (45) reported that ATRA could suppress the adhering ability of RPE cells, and exposure of zebrafish to ATRA could reduce retinal size as a result of increased cell death (46).…”

The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields

“…It is well-known that the overproduction of ROS can cause severe damage to cellular macromolecules, and ROS production is an important intracellular inducer of autophagy [40]. A previous study indicated that ROS regulate autophagy involved in cell survival in endothelial cells [41]. Previous investigations have shown that ROS can stimulate autophagy via the AMPK signaling pathway which is necessary for controlling cellular autophagy under oxidative stress, and subsequently prevent oxidative injury and dysfunction [42].…”

The role and therapeutic potential of melatonin in age‐related ocular diseases

“…Consequently, and considering the melatonin antioxidant effects, its decreased synthesis can contribute to the oxidative insult and finally occurrence of AMD. In fact, aged RPE cells have impaired Nrf2 signaling making them especially vulnerable to oxidative damage . Furthermore, and as some authors point to oxidative stress and Nrf2‐mediated antioxidant defense as promising targets to prevent or treat AMD, exogenous melatonin might also be useful for this purpose (Figure ) .…”

“…In fact, aged RPE cells have impaired Nrf2 signaling making them especially vulnerable to oxidative damage. 270,282 Furthermore, and as some authors point to oxidative stress and Nrf2-mediated antioxidant defense as promising targets to prevent or treat AMD, exogenous melatonin might also be useful for this purpose (Figure 2). 270,276,282,283 Indeed, a preliminary study has demonstrated that the daily use of 3 mg of melatonin, during 3 months, protects the retina and delays macular degeneration.…”