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Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

ABSTRACT: How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE49107 | GEO | 2014/01/30

SECONDARY ACCESSION(S): PRJNA213007

REPOSITORIES: GEO

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Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.

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Project description:Cigarette smoking is the strongest environmental risk factor for developing age-related macular degeneration (AMD), the most common cause of blindness among the elderly in western societies. Despite intensive study, the full impact of smoking on the retinal pigment epithelium (RPE), a central cell type involved in AMD pathobiology, remains unknown. The relative contribution of the known dysfunctional pathways to AMD, at what stage they are most pathogenic, or whether other processes are relevant, is poorly understood, and furthermore, whether they are activated by smoking, is unknown. We performed global RNA-sequencing of the RPE from C57BL/6J mice exposed to chronic cigarette smoke or air for 6 months to identify potential pathogenic and cytoprotective pathways. The RPE transcriptome induced by chronic cigarette smoking exhibited a mixed response of marked suppression of the innate immune response that included the antiviral response with type I and II interferons concurrent with upregulation of cell differentiation and morphogenic gene clusters, suggesting an attempt by the RPE to maintain its differentiated state despite smoke-induced injury. Given that mice exposed to chronic smoke develop early features of AMD, these novel findings are potentially relevant to the transition from aging to AMD.

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Project description:Age related macular degeneration (AMD) is the most prominent cause of blindness in the developed countries. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlaying retinal pigment epithelium (RPE) and choroid endothelial cells. The molecular events that underline the development of these cell types from in utero to adult as well as the progression from the asymptomatic, to intermediate and advanced stages AMD are not yet fully understood. We performed single cell RNA-Sequencing (Seq) of human fetal and adult RPE and choroid, profiling in detail all the cell types and elucidating proliferation, differentiation, antigen pathway presentation and immunomodulation events that characterise the first half of human gestation. Our data demonstrate that progression from fetal to adult state is characterised by an increase in expression of genes involved in oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE and choroid tissues. Single cell comparative transcriptional analysis between an intermediate AMD patient and unaffected subject revealed specific loss of RPE and melanocytes in the macular region. While the CECs loss was not supported by our single cell RNA-Seq data, pathway enrichment analyses supported the onset of apoptosis in these cells, suggesting that during the course of AMD pathogenesis, endothelial cells are the most likely cell type to atrophy in the macula of AMD patients. Together these finds provide a rich resource for enhancing our understanding the development of RPE and choroid and the role they play in AMD progression and pathogenesis

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Expression data from GFP- or GFP Satellite alpha-transfected human retinal pigment epithelia cell line ARPE19

Project description:Oxidative stress (OS) and inflammation play pivotal roles in retinal pigment epithelium (RPE) degeneration and age-related macular degeneration (AMD) pathogenesis. Interleukin 17 (IL17) signaling is a founding pathway regulating inflammatory response, the IL17 ligand has been shown to induce RPE degeneration and is emerging as a potential target for AMD treatment. However, the regulation and function of IL17 receptors are largely unexplored in RPE cells under OS. Here, we identified that IL17RA was significantly upregulated in the presence of OS both in human and mouse RPE cells. We found that OS upregulates expression of reprogramming factor Kruppel-like factor 4 (KLF4), which directly binds to the IL17RA promoter and activates IL17RA transcription, therefore inducing RPE proinflammatory response. Furthermore, our results reveal that KLF4 isoform 2, but not the canonical KLF4 isoform1, is the major isoform in RPE cells that activates IL17RA transcription. Finally, we demonstrate that mRNA level of IL17RA was positively correlated with that of KLF4 isoform2 in AMD patients. Together, our data demonstrates a new regulatory mechanism of IL17RA by KLF4 upon OS exposure, which is likely to play a role in AMD pathogenesis.

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