Abstract
Age-related retinal degenerations, including age-related macular degeneration (AMD), are caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors. The pathogenesis of AMD, deeply linked to the aging process, also involves oxidative stress and inflammatory responses. However, the molecular mechanisms contributing to the shift from healthy aging to AMD are still poorly understood. Since RPE cells in the retina are chronically exposed to a pro-oxidant microenvironment throughout life, we simulated in vivo conditions by growing ARPE-19 cells in the presence of 10 μM H2O2 for several passages. This long-term oxidative insult induced senescence in ARPE-19 cells without affecting cell proliferation. Global proteomic analysis revealed a dysregulated expression in proteins involved in antioxidant response, mitochondrial homeostasis, and extracellular matrix organization. The analyses of mitochondrial functionality showed increased mitochondrial biogenesis and ATP generation and improved response to oxidative stress. The latter, however, was linked to nuclear factor-κB (NF-κB) rather than nuclear factor erythroid 2–related factor 2 (Nrf2) activation. NF-κB hyperactivation also resulted in increased pro-inflammatory cytokines expression and inflammasome activation. Moreover, in response to additional pro-inflammatory insults, senescent ARPE-19 cells underwent an exaggerated inflammatory reaction. Our results indicate senescence as an important link between chronic oxidative insult and detrimental chronic inflammation, with possible future repercussions for therapeutic interventions.
Highlights
Age-related macular degeneration (AMD) is the principal cause of blindness in western countries [1]
We confirmed that ARPE-19 are resistant to acute oxidative stress [23] since doses up to 800 μM only reduced cell viability to 50% of the control
It is well known that the retinal pigmented epithelial (RPE) cell layer is not usually exposed to acute high-dose oxidative stress but, more frequently, to low-level chronical insults [7]
Summary
Age-related macular degeneration (AMD) is the principal cause of blindness in western countries [1]. In 55- to 59-year-old European subjects, the prevalence of early and late AMD is 3.5% (95% confidence interval (CI) 2.1–5.0%) and 0.1% (95% CI 0.04–0.3%), respectively. These data indicate that by 2040 the number of individuals suffering from early AMD will range between 14.9 and 21.5 million [1]. Blindness is caused by the loss of retinal pigmented epithelial (RPE) cells and photoreceptors in large zones of the macula. RPE cells, a monolayer of post-mitotic polarized epithelial cells sandwiched between photoreceptors and the choroid, are devoted to photoreceptor health and function. RPE cells possess specialized functions including phagocytosis of photoreceptor outer segments, light absorption and vitamin A metabolism [2].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
