Smoke Exposure Causes Endoplasmic Reticulum Stress and Lipid Accumulation in Retinal Pigment Epithelium through Oxidative Stress and Complement Activation

Kunchithapautham, Kannan; Atkinson, Carl; Rohrer, Bärbel

doi:10.1074/jbc.m114.564674

Cited by 132 publications

(132 citation statements)

References 69 publications

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“…There is compelling evidence for the production and secretion of cholesterol-containing lipids and lipoprotein particles, secreted at least partly by the RPE (7,8), that are recruited and retained in the aging Bruch's membrane (9)(10)(11)(12)(13)(14). However, there is no unifying explanation of how and why proteins are recruited and retained at the RPE/choriocapillaris interface.…”

mentioning

confidence: 99%

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

113

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Accumulation of protein- and lipid-containing deposits external to the retinal pigment epithelium (RPE) is common in the aging eye, and has long been viewed as the hallmark of age-related macular degeneration (AMD). The cause for the accumulation and retention of molecules in the sub-RPE space, however, remains an enigma. Here, we present fluorescence microscopy and X-ray diffraction evidence for the formation of small (0.5–20 μm in diameter), hollow, hydroxyapatite (HAP) spherules in Bruch’s membrane in human eyes. These spherules are distinct in form, placement, and staining from the well-known calcification of the elastin layer of the aging Bruch’s membrane. Secondary ion mass spectrometry (SIMS) imaging confirmed the presence of calcium phosphate in the spherules and identified cholesterol enrichment in their core. Using HAP-selective fluorescent dyes, we show that all types of sub-RPE deposits in the macula, as well as in the periphery, contain numerous HAP spherules. Immunohistochemical labeling for proteins characteristic of sub-RPE deposits, such as complement factor H, vitronectin, and amyloid beta, revealed that HAP spherules were coated with these proteins. HAP spherules were also found outside the sub-RPE deposits, ready to bind proteins at the RPE/choroid interface. Based on these results, we propose a novel mechanism for the growth, and possibly even the formation, of sub-RPE deposits, namely, that the deposit growth and formation begin with the deposition of insoluble HAP shells around naturally occurring, cholesterol-containing extracellular lipid droplets at the RPE/choroid interface; proteins and lipids then attach to these shells, initiating or supporting the growth of sub-RPE deposits.

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mentioning

confidence: 99%

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Thompson

Reffatto

Bundy³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

106

113

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“…Endoplas-708 mic reticulum (ER) stress and lipid dysregulation can be occurred 709 in mice by long-term smoke inhalation [183]. Cigarette smoke 710 extract can trigger the activation of alternative complement path-711 way in cultured RPE cells, resulting in oxidative stress and lipid 712 deposition [183]. Based on these findings, adverse smoking effect 713 on AMD might be managed by anti-complement therapies.…”

Section: Introductionmentioning

confidence: 97%

“…Amyloid beta will also upregulate MCP-1, which will 621 recruit macrophages and microglia into the subretinal space, and 622 recruited cells will be activated by Amyloid beta to produce var- in cigarette smoke, for example, will damage mitochondrial DNA of 706 cultured RPE cells, increase lysosomal and exocytotic activities, 707 and activate complement pathway components [182]. Endoplas-708 mic reticulum (ER) stress and lipid dysregulation can be occurred 709 in mice by long-term smoke inhalation [183]. Cigarette smoke 710 extract can trigger the activation of alternative complement path-711 way in cultured RPE cells, resulting in oxidative stress and lipid 712 deposition [183].…”

Section: Introductionmentioning

confidence: 99%

Genomic aspects of age-related macular degeneration

Horie‐Inoue

Inoue

2014

Biochemical and Biophysical Research Communications

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“…For example, the lipofuscin that accumulates in the RPE with aging has been shown to inhibit mt function and activate the complement cascade (Vives-Bauza et al, 2008; Zhou et al, 2009). Smoking, one of the strongest modifiable risk factors for AMD, causes mt damage and also activates complement (Mansoor et al, 2014; Wang et al, 2009; Kunchithapautham et al, 2014). The synergistic effect of age-related changes coupled with environmental insults, such as smoking or high fat diet, lowers the threshold for disease and allows the genetic defect to initiate disease.…”

Section: Discussionmentioning

confidence: 99%

Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration

Ferrington

Kapphahn

Leary

et al. 2016

Experimental Eye Research

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Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE.

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Smoke Exposure Causes Endoplasmic Reticulum Stress and Lipid Accumulation in Retinal Pigment Epithelium through Oxidative Stress and Complement Activation

Cited by 132 publications

References 69 publications

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Identification of hydroxyapatite spherules provides new insight into subretinal pigment epithelial deposit formation in the aging eye

Genomic aspects of age-related macular degeneration

Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration

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