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.
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.
Department of Molecular Genetics, University of Lodz, 90-236 Lodz, Poland. ptokarz@biol.uni.lodz.pl.
Paulina
P
Tokarz
Department of Comparative Endocrinology, Medical University of Lodz, 90-752 Lodz, Poland. agnieszka.piastowska@umed.lodz.pl.
Agnieszka Wanda
AW
Piastowska-Ciesielska
Department of Ophthalmology, University of Eastern Finland, 70210 Kuopio, Finland. kai.kaarniranta@kuh.fi.|Department of Ophthalmology, Kuopio University Hospital, 70210 Kuopio, Finland. kai.kaarniranta@kuh.fi.
Kai
K
Kaarniranta
Department of Molecular Genetics, University of Lodz, 90-236 Lodz, Poland. jblasiak@biol.uni.lodz.pl.
Janusz
J
Blasiak
D017209:Apoptosis; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D055213:Retinal Pigment Epithelium / Q000166:cytology; D014212:Tretinoin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; D014212:Tretinoin
AMD; ARPE-19 cells; ATRA; DDR; DNA damage response; ROS; cell death; oxidative stress; retinoic acid