NDLI: Protective effect of autophagy on human retinal pigment epithelial cells against lipofuscin fluorophore A2E: implications for age-related macular degeneration.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhang, J. Bai, Y. Huang, L. Qi, Y. Zhang, Q. Li, S. Wu, Y. Li, X.
Description	Country affiliation: China Author Affiliation: Zhang J ( Department of Ophthalmology, Peking University People's Hospital, Beijing 100044, China.); Bai Y ( Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing 100044, China.); Huang L ( Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Beijing 100044, China.); Qi Y ( Department of Ophthalmology, Peking University People's Hospital, Beijing 100044, China.); Zhang Q ( Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing 100044, China.); Li S ( Beijing Key Laboratory for the Diagnosis and Treatment of Retinal and Choroid Diseases, Beijing 100044, China.); Wu Y ( Department of Ophthalmology, Peking University People's Hospital, Beijing 100044, China.); Li X ( Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing 100044, China.)
Abstract	Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly. Degeneration of retinal pigment epithelial (RPE) cells is a crucial causative factor responsible for the onset and progression of AMD. A2E, a major component of toxic lipofuscin implicated in AMD, is deposited in RPE cells with age. However, the mechanism whereby A2E may contribute to the pathogenesis of AMD remains unclear. We demonstrated that A2E was a danger signal of RPE cells, which induced autophagy and decreased cell viability in a concentration- and time-dependent manner. Within 15 min after the treatment of RPE with 25 µM A2E, the induction of autophagosome was detected by transmission electron microscopy. After continuous incubating RPE cells with A2E, intense punctate staining of LC3 and increased expression of LC3-II and Beclin-1 were identified. Meanwhile, the levels of intercellular adhesion molecule (ICAM), interleukin (IL)1ß, IL2, IL-6, IL-8, IL-17A, IL-22, macrophage cationic peptide (MCP)-1, stromal cell-derived factor (SDF)-1, and vascular endothelial growth factor A (VEGFA) were elevated. The autophagic inhibitor 3-methyladenine (3-MA) and activator rapamycin were also used to verify the effect of autophagy on RPE cells against A2E. Our results revealed that 3-MA decreased the autophagosomes and LC3 puncta induced by A2E, increased inflammation-associated protein expression including ICAM, IL1ß, IL2, IL-6, IL-8, IL-17A, IL-22, and SDF-1, and upregulated VEGFA expression. Whereas rapamycin augmented the A2E-mediated autophagy, attenuated protein expression of inflammation-associated and angiogenic factors, and blocked the Akt/mTOR pathway. Taken together, A2E induces autophagy in RPE cells at the early stage of incubation, and this autophagic response can be inhibited by 3-MA or augmented by rapamycin via the mTOR pathway. The enhancement of autophagy has a protective role in RPE cells against the adverse effects of A2E by reducing the secretion of inflammatory cytokines and VEGFA.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2015.330
Journal	Cell Death and Disease
Volume Number	6
Language	English
Publisher	Nature Publishing Group
Publisher Date	2015-11-12
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, Non-u.s. Gov't Cell Proliferation Retinoids Metabolism Autophagy Retinal Pigment Epithelium Discipline Cell Biology Pathology Etiology Physiology Retinal Pigments Macular Degeneration
Content Type	Text
Resource Type	Article

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