Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration

Pujol-Lereis, Luciana M.; Schäfer, Nicole; Kuhn, Laura B.; Rohrer, Bärbel; Pauly, Diana

doi:10.1007/978-3-319-17121-0_13

Cited by 41 publications

(27 citation statements)

References 31 publications

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“…AMD etiology is complex because it includes the interaction of both genetic components and environmental risk factors [31–35]. Recent studies suggest that oxidative stress and chronic inflammation are elicited by genetic and environmental risk factors such as cigarette smoking, nutritional deficits, sunlight exposure or low ocular melanin to drive the AMD pathogenesis [36]. Here, we evaluated the effect of DJ-1 absence during retinal aging in DJ-1 KO mice.…”

Section: Discussionmentioning

confidence: 99%

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Bonilha

Bell

Rayborn

et al. 2017

Free Radical Biology and Medicine

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Oxidative stress alters physiological function in most biological tissues and can lead to cell death. In the retina, oxidative stress initiates a cascade of events leading to focal loss of RPE and photoreceptors, which is thought to be a major contributing factor to geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative stress under normal and pathological conditions remains largely unknown. A better understanding of the mechanisms involved in regulating RPE and photoreceptors oxidative stress response is greatly needed. To this end we evaluated photoreceptor and RPE changes in mice deficient DJ-1, a protein that is thought to be important in protecting cells from oxidative stress. Young (3 months) and aged (18 months) DJ-1 knockout (DJ-1 KO) and age-matched wild-type mice were examined. In both aged mice scanning laser ophthalmoscopy (SLO) showed the presence of a few autofluorescent foci. The 18 month-old DJ-1 KO retinas were also characterized by a noticeable increase in RPE fluorescence to wild-type. Optical coherence tomography (OCT) imaging demonstrated that all retinal layers were present in the eyes of both DJ-1 KO groups. ERG comparisons showed that older DJ-1 KO mice had reduced sensitivity under dark- and light-adapted conditions compared to age-matched control. Histologically, the RPE contained prominent vacuoles in young DJ-1 KO group with the appearance of enlarged irregularly shaped RPE cells in the older group. These were also evident in OCT and in whole mount RPE/choroid preparations labeled with phalloidin. Photoreceptors in the older DJ-1 KO mice displayed decreased immunoreactivity to rhodopsin and localized reduction in cone markers compared to the wild-type control group. Lower levels of activated Nrf2 were evident in retina/RPE lysates in both young and old DJ-1 KO mouse groups compared to wild-type control levels. Conversely, higher levels of protein carbonyl derivatives and iNOS immunoreactivity were detected in retina/RPE lysates from both young and old DJ-1 KO mice. These results demonstrate that DJ-1 KO mice display progressive signs of retinal/RPE degeneration in association with higher levels of oxidative stress markers. Collectively this analysis indicates that DJ-1 plays an important role in protecting photoreceptors and RPE from oxidative damage during aging.

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Section: Discussionmentioning

confidence: 99%

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Bonilha

Bell

Rayborn

et al. 2017

Free Radical Biology and Medicine

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“…Inhibition of FADS1/2 prevents synthesis of DHA from EPA and blocks EPA-mediated protection of the retina against oxidative stress [32]. Cigarette smoke, one of the most important risk factors for AMD [46], decreases FADS1 and FADS2 activity [47].…”

Section: Discussionmentioning

confidence: 99%

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Ashikawa

Nishimura

Okabe

et al. 2017

Heliyon

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Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1–FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.

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“…This is dependent on light intensity, light quality and exposure time (Wenzel et al, 2005). Several mechanisms are correlated with light-induced photoreceptor degeneration (LD), including an altered retinoid metabolism, increased oxidative stress and immunoreactions (Maeda et al, 2009; Pujol-Lereis et al, 2016). The exact interplay of these cascaded events still needs to be deciphered.…”

Section: Introductionmentioning

confidence: 99%

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

Schäfer

Grosche

Schmitt

et al. 2017

Front. Mol. Neurosci.

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Background: Photoreceptor cell death due to extensive light exposure and induced oxidative-stress are associated with retinal degeneration. A correlated dysregulation of the complement system amplifies the damaging effects, but the local and time-dependent progression of this mechanism is not thoroughly understood.Methods: Light-induced photoreceptor damage (LD) was induced in Balb/c mice with white light illumination either for 24 h with 1000 lux (constant model) or 0.5 h with 5000 lux (acute model). Complement protein and mRNA expression levels were compared at 1 and 3 days post-LD for C1s, complement factor B (CFB), mannose binding lectin A, mannose-binding protein-associated serine protease 1 (MASP-1), C3, C4, C9, and complement factor P in retina and RPE/choroid. Histological analyses visualized apoptosis, microglia/macrophage migration, gliosis and deposition of the complement activation marker C3d. Systemic anaphylatoxin serum concentrations were determined using an ELISA.Results: Apoptosis, gliosis and microglia/macrophage migration into the outer nuclear layer showed similar patterns in both models. Local complement factor expression revealed an early upregulation of complement factor mRNA in the acute and constant light regimen at 1 day post-treatment for c1s, cfb, masp-1, c3, c4 and c9 in the RPE/choroid. However, intraretinal complement mRNA expression for c1s, cfb, c3 and c4 was increased at 1 day in the constant and at 3 days in the acute model. A corresponding regulation on protein level in the retina following both LD models was observed for C3, which was upregulated at 1 day and correlated with increased C3d staining in the ganglion cell layer and at the RPE. In the RPE/choroid C1s-complex protein detection was increased at 3 days after LD irrespectively of the light intensities used.Conclusion: LD in mouse eyes is correlated with local complement activity. The time-dependent local progression of complement regulation on mRNA and protein levels were equivalent in the acute and constant LD model, except for the intraretinal, time-dependent mRNA expression. Knowing the relative time courses of local complement expression and cellular activity can help to elucidate novel therapeutic options in retinal degeneration indicating at which time point of disease complement has to be rebalanced.

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Interrelation Between Oxidative Stress and Complement Activation in Models of Age-Related Macular Degeneration

Cited by 41 publications

References 31 publications

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress

Potential protective function of the sterol regulatory element binding factor 1–fatty acid desaturase 1/2 axis in early-stage age-related macular degeneration

Complement Components Showed a Time-Dependent Local Expression Pattern in Constant and Acute White Light-Induced Photoreceptor Damage

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