scholarly journals Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Dorota Rogińska ◽  
Miłosz P. Kawa ◽  
Ewa Pius-Sadowska ◽  
Renata Lejkowska ◽  
Karolina Łuczkowska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Global Gene Expression ◽  
Complement Component ◽  
Oxidative Stress Marker ◽  
Age Related ◽  
Age Dependent ◽  
Autophagic Activity

The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

scholarly journals Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 793
Author(s):  
Nicole Schäfer ◽  
Hannah N. Wolf ◽  
Anne Enzbrenner ◽  
Juliane Schikora ◽  
Maria Reichenthaler ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment Epithelium ◽  
Structural Integrity ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Complement Component ◽  
Age Related Macular Degeneration ◽  
Complement Components ◽  
Age Related ◽  
Component Production

The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

scholarly journals The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 64
Author(s):  
Annamaria Tisi ◽  
Marco Feligioni ◽  
Maurizio Passacantando ◽  
Marco Ciancaglini ◽  
Rita Maccarone
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Blood Retinal Barrier ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Age Related ◽  
The Impact

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

scholarly journals Acadesine suppresses TNF-α induced complement component 3 (C3), in retinal pigment epithelial (RPE) cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244307
Author(s):  
Nikolaos E. Efstathiou ◽  
Giannis A. Moustafa ◽  
Daniel E. Maidana ◽  
Eleni K. Konstantinou ◽  
Shoji Notomi ◽  
...  
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Complement Component ◽  
Adenosine Kinase ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Rpe Cells ◽  
Age Related ◽  
Tnf Α ◽  
Complement Component 3

Rationale Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness in the developed world. Aging, inflammation and complement dysregulation affecting the retinal pigment epithelium (RPE), are considered significant contributors in its pathogenesis and several evidences have linked tumor necrosis factor alpha (TNF-α) and complement component 3 (C3) with AMD. Acadesine, an analog of AMP and an AMP-activated protein kinase (AMPK) activator, has been shown to have cytoprotective effects in human clinical trials as well as having anti-inflammatory and anti-vascular exudative effects in animals. The purpose of this study was to evaluate if acadesine is able to suppress TNF-α induced C3 in RPE cells. Methods ARPE-19 and human primary RPE cells were cultured and allowed to grow to confluence. TNF-α was used for C3 induction in the presence or absence of acadesine. Small molecule inhibitors and siRNA were used to determine if acadesine exerts its effect via the extracellular or intracellular pathway and to evaluate the importance of AMPK for these effects. The expression level of C3 was determined by immunoblot analysis. Results Acadesine suppresses TNF-α induced C3 in a dose dependent manner. When we utilized the adenosine receptor inhibitor dipyridamole (DPY) along with acadesine, acadesine’s effects were abolished, indicating the necessity of acadesine to enter the cell in order to exert it’s action. However, pretreatment with 5-iodotubericidin (5-Iodo), an adenosine kinase (AK) inhibitor, didn’t prevent acadesine from decreasing TNF-α induced C3 expression suggesting that acadesine does not exert its effect through AMP conversion and subsequent activation of AMPK. Consistent with this, knockdown of AMPK α catalytic subunit did not affect the inhibitory effect of acadesine on TNF-α upregulation of C3. Conclusions Our results suggest that acadesine suppresses TNF-α induced C3, likely through an AMPK-independent pathway, and could have potential use in complement over activation diseases.

JAM-C maintains VEGR2 expression to promote retinal pigment epithelium cell survival under oxidative stress

2017 ◽  
Vol 117 (04) ◽  
pp. 750-757
Author(s):  
Xin Jia ◽  
Chen Zhao ◽  
Qishan Chen ◽  
Yuxiang Du ◽  
Lijuan Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment Epithelium ◽  
Cell Survival ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Photoreceptor Cells ◽  
Rpe Cells

SummaryJunctional adhesion molecule-C (JAM-C) has been shown to play critical roles during development and in immune responses. However, its role in adult eyes under oxidative stress remains poorly understood. Here, we report that JAM-C is abundantly expressed in adult mouse retinae and choroids in vivo and in cultured retinal pigment epithelium (RPE) and photoreceptor cells in vitro. Importantly, both JAM-C expression and its membrane localisation are downregulated by H2O2-induced oxidative stress. Under H2O2-induced oxidative stress, JAM-C is critically required for the survival of human RPE cells. Indeed, loss of JAM-C by siRNA knockdown decreased RPE cell survival. Mechanistically, we show that JAM-C is required to maintain VEGFR2 expression in RPE cells, and VEGFR2 plays an important role in keeping the RPE cells viable since overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown and increased RPE survival. We further show that JAM-C regulates VEGFR2 expression and, in turn, modulates p38 phosphorylation. Together, our data demonstrate that JAM-C plays an important role in maintaining VEGR2 expression to promote RPE cell survival under oxidative stress. Given the vital importance of RPE in the eye, approaches that can modulate JAM-C expression may have therapeutic values in treating diseases with impaired RPE survival.

scholarly journals PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

2018 ◽  
Vol 19 (8) ◽  
pp. 2317 ◽  
Author(s):  
Kai Kaarniranta ◽  
Jakub Kajdanek ◽  
Jan Morawiec ◽  
Elzbieta Pawlowska ◽  
Janusz Blasiak
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Mitochondrial Biogenesis ◽  
Vision Loss ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sirtuin 1 ◽  
Age Related Macular Degeneration ◽  
Rpe Cells ◽  
Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

scholarly journals Photo-damage, photo-protection and age-related macular degeneration

2015 ◽  
Vol 14 (9) ◽  
pp. 1560-1577 ◽  
Author(s):  
Melisa D. Marquioni-Ramella ◽  
Angela M. Suburo
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Molecular Targets ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Photo Damage ◽  
Effect Of Light

The course of Age-related Macular Degeneration (AMD) is described as the effect of light (400–580 nm) on various molecular targets in photoreceptors and the retinal pigment epithelium (RPE). Photo-damage is followed by inflammation, increasing oxidative stress and, probably, unveiling new photosensitive molecules.

scholarly journals Oxidative stress-mediated TXNIP loss causes RPE dysfunction

2019 ◽  
Vol 51 (10) ◽  
pp. 1-13 ◽  
Author(s):  
Min Ji Cho ◽  
Sung-Jin Yoon ◽  
Wooil Kim ◽  
Jongjin Park ◽  
Jangwook Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Function ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Common Factor ◽  
Age Related Macular Degeneration ◽  
Autophagic Flux ◽  
Blood Retinal Barrier ◽  
Rpe Cells ◽  
Age Related

Abstract The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.

scholarly journals Dietary Supplementation with Beta-Cryptoxanthin (BCX) Protects Against Light-Induced Retinal Damage

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 126-126
Author(s):  
Deshanie Rai ◽  
Kazim Sahin ◽  
Kazim Sahin ◽  
Emre Sahin ◽  
Mehmet Tuzcu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Angiogenic Factor ◽  
Retinal Damage ◽  
Waste Products ◽  
Health Technologies ◽  
Retinal Tissue ◽  
Age Related ◽  
Markers Of Oxidative Stress

Abstract Objectives The retinal pigment epithelium (RPE) regulates the transport of nutrients and waste products to and from the retina and protects against light and oxidative stress. Structural or physiological dysfunction of RPE leads to retinal conditions such as age-related eye disease (ARED). It is well-established that artificial and natural light is an important factor in the progression of ARED as it can induce oxidative damage and photochemical lesions. Recently, the use of LED in general lighting has raised concerns regarding the effects of this light source on the RPE. The goal was to investigate whether beta-cryptoxanthin, an efficient pro-vitamin A carotenoid can exert protective effects against LED-induced RPE cell damage. Methods Rats were fed with BCX for 4 weeks at a dose of 2 and 4 mg/kg body weight followed by retinal damage by exposing the eye to bright LED light for 48 hrs. Commercially available white LED sources, which are widely used in rat housing studies was used to induce retinal damage. Animals were sacrificed at the end of the study and retinal tissue and blood samples were collected and evaluated for retinal damage and markers of oxidative stress. Results BCX supplementation significantly reduced retinal damage as demonstrated by histopathology measurements including total retinal thickness, outer nuclear layer thickness, and swelling. Similarly, markers of oxidative stress including serum and retinal tissue levels of malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase were beneficially modulated by BCX supplementation. In parallel, BCX supplementation reduced inflammatory markers (IL-1β, IL-6, NF-κB), angiogenic factor VEGF, apoptotic proteins (Caspase-3, GAP43, GFAP, NCAM, HO-1) and mitochondrial stress markers (ATF4, ATF6, Grp78, Grp97) in retinal tissue. Conclusions Our study supports that oral supplementation of BCX dose-dependently exerts a protective effect against retinal damage induced by high-intensity light in a rat model by reducing oxidative stress, inflammation, angigogenesis and protection against mitochondrial DNA damage. BCX dietary intakes and supplementation throughout all stages of life can help protect against ARED that may start early in life. Funding Sources OmniActive Health Technologies.

scholarly journals Human iPS cell derived RPE strips for secure delivery of graft cells at a target place with minimal surgical invasion

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mitsuhiro Nishida ◽  
Yuji Tanaka ◽  
Yo Tanaka ◽  
Satoshi Amaya ◽  
Nobuyuki Tanaka ◽  
...  
Keyword(s):  
Target Location ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Cell Sheet ◽  
Invasive Procedure ◽  
Age Related Macular Degeneration ◽  
Target Area ◽  
Ips Cell ◽  
Age Related

AbstractSeveral clinical studies have been conducted into the practicality and safety of regenerative therapy using hESC/iPSC-retinal pigment epithelium (RPE) as a treatment for the diseases including age-related macular degeneration. These studies used either suspensions of RPE cells or an RPE cell sheet. The cells can be injected using a minimally invasive procedure but the delivery of an intended number of cells at an exact target location is difficult; cell sheets take a longer time to prepare, and the surgical procedure is invasive but can be placed at the target area. In the research reported here, we combined the advantages of the two approaches by producing a quickly formed hiPSC-RPE strip in as short as 2 days. The strip readily expanded into a monolayer sheet on the plate, and after transplantation in nude rats, it showed a potency to partly expand with the correct apical/basal polarity in vivo, although limited in expansion area in the presence of healthy host RPE. The strip could be injected into a target area in animal eyes using a 24G canula tip.

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