Oxidative Stress Induces Senescence in Cultured RPE Cells

Aryan, Nona; Betts-Obregon, Brandi S; Perry, George; Tsin, Andrew

doi:10.2174/1874205x01610010083

Cited by 26 publications

(19 citation statements)

References 12 publications

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“…Senescent cells secret numerous kinds of pro-inflammatory cytokines, chemokines, growth factors and proteases, exemplifying what is referred to as a senescence-associated secretory phenotype (SASP) [ 23 ]. Further, oxidative stress also plays an important role in RPE senescence [ 24 – 26 ]. Congruent with this, we treated additional ARPE-19 cells with 10 µM FK866 for 72 h, the dose and time-point most effective at reducing NAD + and promoting cellular senescence without robust toxicity, and monitored them for expression of the pro-inflammatory cytokines IL-6 and IL-8 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

Jadeja

Powell

Jones

et al. 2018

Aging

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Retinal pigment epithelium (RPE) performs numerous functions critical to retinal health and visual function. RPE senescence is a hallmark of aging and degenerative retinal disease development. Here, we evaluated the temporal expression of key nicotinamide adenine dinucleotide (NAD+)-biosynthetic genes and associated levels of NAD+, a principal regulator of energy metabolism and cellular fate, in mouse RPE. NAD+ levels declined with age and correlated directly with decreased nicotinamide phosphoribosyltransferase (NAMPT) expression, increased expression of senescence markers (p16INK4a, p21Waf/Cip1, ApoJ, CTGF and β-galactosidase) and significant reductions in SIRT1 expression and activity. We simulated in vitro the age-dependent decline in NAD+ and the related increase in RPE senescence in human (ARPE-19) and mouse primary RPE using the NAMPT inhibitor FK866 and demonstrated the positive impact of NAD+-enhancing therapies on RPE cell viability. This, we confirmed in vivo in the RPE of mice injected sub-retinally with FK866 in the presence or absence of nicotinamide mononucleotide. Our data confirm the importance of NAD+ to RPE cell biology normally and in aging and demonstrate the potential utility of therapies targeting NAMPT and NAD+ biosynthesis to prevent or alleviate consequences of RPE senescence in aging and/or degenerative retinal diseases in which RPE dysfunction is a crucial element.

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Section: Resultsmentioning

confidence: 99%

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

Jadeja

Powell

Jones

et al. 2018

Aging

View full text Add to dashboard Cite

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“…However, if the majority of RPE cells are senescent, the compensating mechanisms can fail and lead to AMD progression. Oxidative stress has been shown to induce senescence in the RPE cells, but the exact mechanism has not been clarified (Aryan et al, 2016). The release of pro-inflammatory cytokines and ROS by senescent cells, DNA damage-induced senescence, induction of senescence in neighboring cells, as well as the interplay between senescence and autophagy are considered to regulate RPE degeneration (Sikora et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Can vitamin D protect against age-related macular degeneration or slow its progression?

et al. 2019

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Dietary vitamin D plays an important role in maintaining proper vision. Age-related macular degeneration (AMD) is a complex eye disease with unknown pathogenesis. Studies on dietary supplementation and AMD occurrence and progression have produced conflicting results. In its advanced stage, AMD may be associated with apoptosis, pyroptosis or necroptosis of retinal cells. Vitamin D has been reported to play a role in modulating each of these programmed death pathways. Vitamin D is a modulator of the immune system and it acts synergistically with two members of the regulators of complement activation family H and I, whose specific variants are the most important genetic factors for AMD pathogenesis. Angiogenesis is an essential component of the neovascular form of AMD, the most devastating type of the disease and vitamin D is reputed to possess antiangiogenic properties. Cellular DNA damage response is weakened in AMD patients and so it is another process that can be modulated by vitamin D. Finally, impaired autophagy is claimed to play a role in AMD and emerging evidence suggests that vitamin D can influence autophagy. Therefore, several pathways of vitamin D metabolism and AMD pathogenesis overlap, suggesting that vitamin D could modulate the course of AMD.

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“…Lastly, we wished to test the effects of CS on cellular senescence. Senescence of RPE cells has been identified in many studies as a key mechanism in AMD pathogenesis [ 43 , 44 ], and has been shown to be induced by oxidative stress [ 45 , 46 ]. In our study, we found that CS induces senescence in ARPE-19 cells, as seen by an increase in SA-β-galactosidase positive cells ( Fig 7A and 7B ), a result that has been studied before [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells

2017

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Age related macular degeneration (AMD) is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS) initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE) cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE) induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01), which was subsequently mitigated through cysteamine (p < 0.01) or fisetin (p < 0.05) treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05) that were cleared- off with cysteamine (p < 0.05) or fisetin (p < 0.05). Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization) and autophagy-flux impairment was significantly (p<0.01) mitigated by cysteamine (p<0.05) or fisetin (p<0.05) treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001) while impacting cell viability (p < 0.001), which was quantified using CMH2DCFDA-dye (ROS) and MTS (proliferation) or propodium iodide staining (cell viability) assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05) and diminished cell viability (p < 0.05). Lastly, CSE was found to induce cellular senescence (p < 0.001), which was significantly ameliorated by cysteamine (p < 0.001) or fisetin (p < 0.001). In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover, autophagy-inducing drugs such as cysteamine or fisetin can ameliorate AMD pathogenesis mechanisms that warrant further investigation in pre-clinical murine models.

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Oxidative Stress Induces Senescence in Cultured RPE Cells

Cited by 26 publications

References 12 publications

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

Can vitamin D protect against age-related macular degeneration or slow its progression?

Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells

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