Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration

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Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration

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dc.contributor.author Marazita, Mariela C.
dc.contributor.author Dugour, Andrea
dc.contributor.author Marquioni Ramella, Melisa D.
dc.contributor.author Figueroa, Juan M.
dc.contributor.author Suburo, Angela
dc.date.accessioned 2019-11-01T20:43:40Z
dc.date.available 2019-11-01T20:43:40Z
dc.date.issued 2016-04-01
dc.identifier.citation Redox Biol. 2016 Apr; 7: 78–87 en_US
dc.identifier.issn 2213-2317
dc.identifier.uri https://riu.austral.edu.ar/handle/123456789/744
dc.description.abstract Oxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-β-galactosidase (SA-β-Gal) staining, and p16INK4a and p21Waf-Cip1 protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking. en_US
dc.language.iso en en_US
dc.publisher Elsevier B.V. ScienceDirect en_US
dc.subject Oxidative stress en_US
dc.subject multifactorial disease en_US
dc.subject senescence en_US
dc.title Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: Implications for Age-related Macular Degeneration en_US
dc.type Article en_US


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