Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina

Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.

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A Novel HDL-Mimetic Peptide HM-10/10 Protects RPE and Photoreceptors in Murine Models of Retinal Degeneration

International Journal of Molecular Sciences ◽

10.3390/ijms20194807 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4807 ◽

Cited By ~ 1

Author(s):

Feng Su ◽

Christine Spee ◽

Eduardo Araujo ◽

Eric Barron ◽

Mo Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Retinal Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Disease ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Mimetic Peptide ◽

Age Related

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD. Oxidative stress plays a key role in the development of AMD. We generated a chimeric high-density lipoprotein (HDL), mimetic peptide named HM-10/10, with anti-oxidant properties and investigated its potential for the treatment of retinal disease using cell culture and animal models of RPE and photoreceptor (PR) degeneration. Treatment with HM-10/10 peptide prevented human fetal RPE cell death caused by tert-Butyl hydroperoxide (tBH)-induced oxidative stress and sodium iodate (NaIO3), which causes RPE atrophy and is a model of geographic atrophy in mice. We also show that HM-10/10 peptide ameliorated photoreceptor cell death and significantly improved retinal function in a mouse model of N-methyl-N-nitrosourea (MNU)-induced PR degeneration. Our results demonstrate that HM-10/10 protects RPE and retina from oxidant injury and can serve as a potential therapeutic agent for the treatment of retinal degeneration.

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Protection of Kaempferol on Oxidative Stress-Induced Retinal Pigment Epithelial Cell Damage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1610751 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 32

Author(s):

Weiwei Du ◽

Yuanlong An ◽

Xiangdong He ◽

Donglei Zhang ◽

Wei He

Keyword(s):

Oxidative Stress ◽

Retinal Degeneration ◽

Cell Damage ◽

Retinal Pigment Epithelial Cell ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Sodium Iodate ◽

Rpe Cells ◽

Age Related

The protection of retinal pigment epithelium (RPE) injury plays an important role in the prevention of or in delaying the pathological progress of retinal degeneration diseases, like age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa. Oxidative stress has been identified as a major inducer of RPE injury, which eventually could lead to a loss of vision. Kaempferol is a natural flavonoid widely distributed in many edible plants, fruits, and traditional medicines and has been reported to have antioxidant, anti-inflammatory, anticancer, and antimicrobial activities. The present study demonstrates that the total antioxidant capacity of kaempferol is approximately two times stronger than that of lutein which is also a natural antioxidant that is widely used in the prevention or treatment of AMD. Our data indicates that kaempferol protects human RPE cells (ARPE-19) from hydrogen peroxide- (H2O2-) induced oxidative cell damage and apoptosis through the signaling pathways involving Bax/Bcl-2 and caspase-3 molecules proofed by real-time PCR and Western blot results. Kaempferol also inhibits the upregulated vascular endothelial growth factor (VEGF) mRNA expression levels induced by H2O2 in ARPE-19 cells and affects the oxidation and antioxidant imbalanced system in ARPE-19 cells treated by H2O2 through the regulations of both the activities of reactive oxygen species (ROS) and superoxide dismutase (SOD). Furthermore, our in vivo experimental results show that in sodium iodate-induced retinal degeneration rat model, kaempferol could protect sodium iodate-induced pathological changes of retina tissue and retinal cells apoptosis as well as the upregulated VEGF protein expression in RPE cells. In summary, these novel findings demonstrate that kaempferol could protect oxidative stressed-human RPE cell damage through its antioxidant activity and antiapoptosis function, suggesting that kaempferol has a potential role in the prevention and therapeutic treatment of AMD or other retinal diseases mediated by oxidative stress.

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Potential Treatment of Retinal Diseases with Iron Chelators

Pharmaceuticals ◽

10.3390/ph11040112 ◽

2018 ◽

Vol 11 (4) ◽

pp. 112 ◽

Cited By ~ 13

Author(s):

Wanting Shu ◽

Joshua Dunaief

Keyword(s):

Retinal Degeneration ◽

Therapeutic Potential ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Body ◽

Age Related Macular Degeneration ◽

Hereditary Diseases ◽

Iron Chelators ◽

Excess Iron ◽

Age Related

Iron is essential for life, while excess iron can be toxic. Iron generates hydroxyl radical, which is the most reactive free radical, causing oxidative stress. Since iron is absorbed through the diet but not excreted from the body, it accumulates with age in tissues, including the retina, consequently leading to age-related toxicity. This accumulation is further promoted by inflammation. Hereditary diseases such as aceruloplasminemia, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, and posterior column ataxia with retinitis pigmentosa involve retinal degeneration associated with iron dysregulation. In addition to hereditary causes, dietary or parenteral iron supplementation has been recently reported to elevate iron levels in the retinal pigment epithelium (RPE) and promote retinal degeneration. Ocular siderosis from intraocular foreign bodies or subretinal hemorrhage can also lead to retinopathy. Evidence from mice and humans suggests that iron toxicity may contribute to age-related macular degeneration pathogenesis. Iron chelators can protect photoreceptors and RPE in various mouse models. The therapeutic potential for iron chelators is under investigation.

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Origins of Ghost Drusen: A follow-up Analysis

Ophthalmology Point of Care ◽

10.5301/oapoc.0000011 ◽

2017 ◽

Vol 1 (1) ◽

pp. oapoc.0000011

Author(s):

Caroline Bottin ◽

Olivia Zambrowski ◽

Giuseppe Querques ◽

Salomon Yves Cohen ◽

Mayer Srour ◽

...

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Geographic Atrophy ◽

Primary Lesion ◽

Age Related Macular Degeneration ◽

Age Related ◽

Soft Drusen ◽

Initial Lesions ◽

Sd Oct

Purpose Ghost drusen (GD) are pyramidal or dome-shaped retinal pigment epithelium elevations observed in some geographic atrophy (GA) areas in the context of age-related macular degeneration (AMD). The purpose was to investigate the first morphologic features preceding GD on spectral-domain optical coherence tomography (SD-OCT) on patients with GA associated with AMD. Methods A retrospective observational study was performed on a series of patients with GA that had at least 3 years of follow-up. Using the follow-up tool of SD-OCT, we tracked the initial lesions that could lead to GD. Results Among 442 patients with GA, 37 had well defined GD (8%). We included the 17/37 patients (31 eyes) with at least 3 years of follow-up for analysis, which led to a total of 582 counted GD. Most GD were already present at the first visit, and remained stable. However, on 13 of the 582 analyzed GD (2.2%), soft drusen were shown as the initial lesion, which progressively turned into GD. Conclusions GD were observed in less than 10% of eyes with GA. None of the ghost drusen turned into another shaped lesion, suggesting that GD is a possible final stage of evolution. In a few cases, large drusen were shown as the primary lesion that progressed into GD.

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Quantitative metabolomics of photoreceptor degeneration and the effects of stem cell-derived retinal pigment epithelium transplantation

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2015.0376 ◽

2016 ◽

Vol 374 (2079) ◽

pp. 20150376 ◽

Cited By ~ 7

Author(s):

Junhua Wang ◽

Peter D. Westenskow ◽

Mingliang Fang ◽

Martin Friedlander ◽

Gary Siuzdak

Keyword(s):

Stem Cell ◽

Retinal Pigment Epithelium ◽

Retinal Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Photoreceptor Degeneration ◽

Quantitative Metabolomics ◽

Fatty Acid Amides ◽

Age Related

Photoreceptor degeneration is characteristic of vision-threatening diseases including age-related macular degeneration. Photoreceptors are metabolically demanding cells in the retina, but specific details about their metabolic behaviours are unresolved. The quantitative metabolomics of retinal degeneration could provide valuable insights and inform future therapies. Here, we determined the metabolomic ‘fingerprint’ of healthy and dystrophic retinas in rat models using optimized metabolite extraction techniques. A number of classes of metabolites were consistently dysregulated during degeneration: vitamin A analogues, fatty acid amides, long-chain polyunsaturated fatty acids, acyl carnitines and several phospholipid species. For the first time, a distinct temporal trend of several important metabolites including DHA (4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid), all- trans -retinal and its toxic end-product N -retinyl- N -retinylidene-ethanolamine were observed between healthy and dystrophic retinas. In this study, metabolomics was further used to determine the temporal effects of the therapeutic intervention of grafting stem cell-derived retinal pigment epithelium (RPE) in dystrophic retinas, which significantly prevented photoreceptor atrophy in our previous studies. The result revealed that lipid levels such as phosphatidylethanolamine in eyes were restored in those animals receiving the RPE grafts. In conclusion, this study provides insight into the metabolomics of retinal degeneration, and further understanding of the efficacy of RPE transplantation. This article is part of the themed issue ‘Quantitative mass spectrometry’.

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Clinical and Functional Characteristics of Secondary Geographic Atrophy Against the Background of Exudative Age-Related Macular Degeneration

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1557 ◽

2021 ◽

Vol 76 (4) ◽

pp. 384-393

Author(s):

Vladimir V. Neroev ◽

Marina V. Zueva ◽

Natalia V. Neroeva ◽

Ludmila A. Katargina ◽

Oksana A. Losanova ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Antiangiogenic Therapy ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Age Related ◽

Flicker Erg ◽

Wet Amd

Background.Studies demonstrate the need for long-term follow-up of patients with wet age-related macular degeneration (AMD) treated with inhibitors of angiogenesis to monitor long-term vision outcomes and assess the safety of antiangiogenic therapy in relation to the risk of secondary geographic atrophy. Aims to determine the characteristic clinical and functional signs of secondary GA that developed against the background of wet AMD. Methods.In 22 patients (25 eyes) with wet AMD and 18 healthy subjects comparable in age and sex standard ophthalmological and instrumental studies were performed and photopic electroretinograms (ERGs) were recorded according to ISCEV standards, flicker-ERGs, multifocal ERGs and electrooculogram. Results.The appearance of the area of secondary atrophy against the background of wet AMD in eyes treated with inhibitors of angiogenesis is clinically indistinguishable from areas of geographic atrophy that developed as an outcome of dry AMD. The ERG-signs of secondary atrophy are described, which are similar to the biomarkers of primary atrophy and specifically differ from them. Secondary atrophy is characterized by the dependence of the increase in the b/a ratio on the atrophic area, reducing of the 8.3 Hz-flicker-ERG amplitude in the absence of 24 Hz-flicker ERG changes. In eyes with secondary atrophy, a significant decrease in the density of the multifocal ERG P1-peak was shown not only in the first hexagon but also in the parafoveal zone. The electrooculography results showed a sharper dark troughs decrease in with an increase in Ardens ratio in patients with secondary atrophya on the background of wet AMD, in contrast to the previously described changes in primary geographic atrophy. Conclusion.Comparison of the change in the b/a ratio with secondary atrophy area in patients with wet AMD may have clinical implications for assessing retinal dysfunction and predicting visual function. Secondary atrophy is associated with a pronounced inhibition of photoreceptor activity with better preservation of cone bipolar cells. The ERG and electrooculography data taking together indicate a more significant dysfunction of the retinal pigment epithelium in GA against the background of wet AMD and the associated deterioration of photoreceptor function than the changes characterizing primary geographic atrophy.

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Choriocapillaris Loss in Advanced Age-Related Macular Degeneration

Journal of Ophthalmology ◽

10.1155/2018/8125267 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 16

Author(s):

Carlos A. Moreira-Neto ◽

Eric M. Moult ◽

James G. Fujimoto ◽

Nadia K. Waheed ◽

Daniela Ferrara

Keyword(s):

Macular Degeneration ◽

Current Knowledge ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Advanced Age ◽

Tissue Loss ◽

Age Related

The purpose of this review is to summarize the current knowledge on choriocapillaris loss in advanced age macular degeneration (AMD). Several histopathological studies in animal models and human eyes had showed that the choriocapillaris density decreases with age. However, the role of choriocapillaris loss is still unclear in AMD and its advanced forms, either choroidal neovascularization (CNV) or geographic atrophy (GA). Some authors have hypothesized that choriocapillaris loss might precede overt retinal pigment epithelium atrophy. Others have hypothesized that deposition of complement complexes on and around the choriocapillaris could be related to the tissue loss observed in early AMD. The development of imaging modalities, such as optical coherence tomography angiography (OCTA), have led to a better understanding of underlying physiopathological mechanisms in AMD. OCTA showed atrophy of choriocapillaris underneath and beyond the region of photoreceptors and RPE loss, in agreement with previous histopathologic studies. The evolution of OCTA technology suggests that CNV seems to originate from regions of severe choriocapillaris alteration. Significant progress has been made in the understanding of development and progression of GA and CNV. In vivo investigation of the choriocapillaris using OCTA may lead to new insights related to underlying disease mechanisms in AMD.

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Complement System and Potential Therapeutics in Age-Related Macular Degeneration

International Journal of Molecular Sciences ◽

10.3390/ijms22136851 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6851

Author(s):

Young-Gun Park ◽

Yong-Soo Park ◽

In-Beom Kim

Keyword(s):

Macular Degeneration ◽

Complement System ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Retinal Pigment Epithelium Cell ◽

Immune Surveillance ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Age Related ◽

The Complement System

Age-related macular degeneration (AMD) is a complex multifactorial disease characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). The complement system is an intrinsic component of innate immunity. There has been growing evidence that the complement system plays an integral role in maintaining immune surveillance and homeostasis in AMD. Based on the association between the genotypes of complement variants and AMD occurrence and the presence of complement in drusen from AMD patients, the complement system has become a therapeutic target for AMD. However, the mechanism of complement disease propagation in AMD has not been fully understood. This concise review focuses on an overall understanding of the role of the complement system in AMD and its ongoing clinical trials. It provides further insights into a strategy for the treatment of AMD targeting the complement system.

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NLRP3 Inflammasome: Activation and Regulation in Age-Related Macular Degeneration

Mediators of Inflammation ◽

10.1155/2015/690243 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 35

Author(s):

Jiangyuan Gao ◽

Ruozhou Tom Liu ◽

Sijia Cao ◽

Jing Z. Cui ◽

Aikun Wang ◽

...

Keyword(s):

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Elderly ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Inflammasome Activation ◽

Related Factors ◽

Rpe Cells ◽

Age Related

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the elderly in industrialized countries. AMD is a multifactorial disease influenced by both genetic and environmental risk factors. Progression of AMD is characterized by an increase in the number and size of drusen, extracellular deposits, which accumulate between the retinal pigment epithelium (RPE) and Bruch’s membrane (BM) in outer retina. The major pathways associated with its pathogenesis include oxidative stress and inflammation in the early stages of AMD. Little is known about the interactions among these mechanisms that drive the transition from early to late stages of AMD, such as geographic atrophy (GA) or choroidal neovascularization (CNV). As part of the innate immune system, inflammasome activation has been identified in RPE cells and proposed to be a causal factor for RPE dysfunction and degeneration. Here, we will first review the classic model of inflammasome activation, then discuss the potentials of AMD-related factors to activate the inflammasome in both nonocular immune cells and RPE cells, and finally introduce several novel mechanisms for regulating the inflammasome activity.

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Tracking the Transplanted Neurosphere in Retinal Pigment Epithelium Degeneration Model

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2021.12.4.2230.1 ◽

2021 ◽

Vol 12 (4) ◽

pp. 523-532

Author(s):

Hamid Aboutaleb Kadkhodaeian1 ◽

◽

Amir Salati ◽

Mojtaba Ansari ◽

Vajihe Taghdiri Nooshabadi ◽

...

Keyword(s):

Stem Cells ◽

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Study Data ◽

Age Related Macular Degeneration ◽

Sodium Iodate ◽

Neural Lineage ◽

Age Related ◽

Stromal Stem Cells

Introduction: Retinal Pigment Epithelium (RPE) layer deterioration is a leading cause of Age-Related Macular Degeneration (AMD), i.e., the most significant reason for irreversible blindness. The present study aimed to track the Neurosphere-Derived (NS) from Bone Marrow Stromal Stem Cells (BMSCs) grafted into the sub-retinal space (destruction of the RPE layer by sodium iodate). Methods: RPE degeneration model was performed using the injection of 5% sodium iodate performed in the retro-orbital sinus of Wistar rats. BMSCs were extracted from the examined rat femur and induced into NS, using EGF, bFGF, and B27. BrdU-NS labeled cells were transplanted into the sub-retinal space. For detecting BMSCs and NS markers, immunocytochemistry was performed. Moreover, immunohistochemical was conducted for tracking the transplanted cells in the RPE and sensory retina. Results: The immunocytochemistry of BMSCs cells displayed the expression of mesenchymal stem cells markers (CD90; 99%±1), CD166 (98%±2), CD44 (99%±1). Additionally, the expression of neural lineage markers in NS, such as SOX2, OCT4, Nanog, Nestin, and Neurofilaments (68, 160, 200) revealed the differentiation from BMSCs. Tracking BrdU-NS labeled suggested these aggregations in most layers of the retina. Conclusion: Our study data indicated that BMSCs derived neurosphere had the potential to migrate in injured retinal and integrate into the neurosensory retina. These data can be useful in finding safe cells for replacement therapy in AMD.

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