Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-κB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD.
Highlights
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people in the United States and other developed countries
The results showed that A2E was phagocytized by Retinal pigment epithelium (RPE) cells (Fig. SP1)
At 25 μM A2E, blue light photosensitization further decreased cell viability. This A2E concentration is similar to the amount of A2E present in RPE cells harvested from human donor eyes[18]
Summary
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people in the United States and other developed countries. It is estimated that by 2020, nearly 80 million people will be affected by the disease[1]. Retinal pigment epithelium (RPE) cells exist as a monolayer between the neural retina and the choroidal vasculature. An important function of RPE cells is to phagocytose the shedding outer segment discs of the photoreceptors to maintain normal visual function. RPE cells secrete growth factors, such as fibroblast growth factors, transforming growth factor-beta, insulin-like growth factor-I, ciliary neurotrophic factor, vascular endothelial growth factor, and pigment epithelium-derived factor to maintain retina homeostasis[4]. A decrease in RPE-mediated phagocytosis leads to an accumulation of lipofuscin, which
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