scholarly journals Metabolism in the Zebrafish Retina

2021 ◽  
Vol 9 (1) ◽  
pp. 10
Author(s):  
Natalia Jaroszynska ◽  
Philippa Harding ◽  
Mariya Moosajee
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Therapeutic Approaches ◽  
Retinal Photoreceptors ◽  
Sufficient Energy ◽  
Metabolic Products ◽  
Sight Loss ◽  
Choroidal Vasculature ◽  
The Brain

Retinal photoreceptors are amongst the most metabolically active cells in the body, consuming more glucose as a metabolic substrate than even the brain. This ensures that there is sufficient energy to establish and maintain photoreceptor functions during and after their differentiation. Such high dependence on glucose metabolism is conserved across vertebrates, including zebrafish from early larval through to adult retinal stages. As the zebrafish retina develops rapidly, reaching an adult-like structure by 72 hours post fertilisation, zebrafish larvae can be used to study metabolism not only during retinogenesis, but also in functionally mature retinae. The interplay between rod and cone photoreceptors and the neighbouring retinal pigment epithelium (RPE) cells establishes a metabolic ecosystem that provides essential control of their individual functions, overall maintaining healthy vision. The RPE facilitates efficient supply of glucose from the choroidal vasculature to the photoreceptors, which produce metabolic products that in turn fuel RPE metabolism. Many inherited retinal diseases (IRDs) result in photoreceptor degeneration, either directly arising from photoreceptor-specific mutations or secondary to RPE loss, leading to sight loss. Evidence from a number of vertebrate studies suggests that the imbalance of the metabolic ecosystem in the outer retina contributes to metabolic failure and disease pathogenesis. The use of larval zebrafish mutants with disease-specific mutations that mirror those seen in human patients allows us to uncover mechanisms of such dysregulation and disease pathology with progression from embryonic to adult stages, as well as providing a means of testing novel therapeutic approaches.

scholarly journals Nanocarriers, Progenitor Cells, Combinational Approaches, and New Insights on the Retinal Therapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1776
Author(s):  
Elham Pishavar ◽  
Hongrong Luo ◽  
Johanna Bolander ◽  
Antony Atala ◽  
Seeram Ramakrishna
Keyword(s):  
Drug Delivery ◽  
Progenitor Cells ◽  
Transfection Efficiency ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Therapeutic Approaches ◽  
Age Related ◽  
Nanofibrous Scaffolds ◽  
The Stability

Progenitor cells derived from the retinal pigment epithelium (RPECs) have shown promise as therapeutic approaches to degenerative retinal disorders including diabetic retinopathy, age-related macular degeneration and Stargardt disease. However, the degeneration of Bruch’s membrane (BM), the natural substrate for the RPE, has been identified as one of the major limitations for utilizing RPECs. This degeneration leads to decreased support, survival and integration of the transplanted RPECs. It has been proposed that the generation of organized structures of nanofibers, in an attempt to mimic the natural retinal extracellular matrix (ECM) and its unique characteristics, could be utilized to overcome these limitations. Furthermore, nanoparticles could be incorporated to provide a platform for improved drug delivery and sustained release of molecules over several months to years. In addition, the incorporation of tissue-specific genes and stem cells into the nanostructures increased the stability and enhanced transfection efficiency of gene/drug to the posterior segment of the eye. This review discusses available drug delivery systems and combination therapies together with challenges associated with each approach. As the last step, we discuss the application of nanofibrous scaffolds for the implantation of RPE progenitor cells with the aim to enhance cell adhesion and support a functionally polarized RPE monolayer.

scholarly journals OCT imaging of rod mitochondrial respiration in vivo

2021 ◽  
pp. 153537022110137
Author(s):  
Bruce A Berkowitz ◽  
Haohua Qian
Keyword(s):  
Signaling Pathway ◽  
Mitochondrial Respiration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
The Body ◽  
Subretinal Space ◽  
Outer Retina ◽  
Water Efflux ◽  
Resolution Imaging

There remains a need for high spatial resolution imaging indices of mitochondrial respiration in the outer retina that probe normal physiology and measure pathogenic and reversible conditions underlying loss of vision. Mitochondria are involved in a critical, but somewhat underappreciated, support system that maintains the health of the outer retina involving stimulus-evoked changes in subretinal space hydration. The subretinal space hydration light–dark response is important because it controls the distribution of vision-critical interphotoreceptor matrix components, including anti-oxidants, pro-survival factors, ions, and metabolites. The underlying signaling pathway controlling subretinal space water management has been worked out over the past 30 years and involves cGMP/mitochondria respiration/pH/RPE water efflux. This signaling pathway has also been shown to be modified by disease-generating conditions, such as hypoxia or oxidative stress. Here, we review recent advances in MRI and commercially available OCT technologies that can measure stimulus-evoked changes in subretinal space water content based on changes in the external limiting membrane-retinal pigment epithelium region. Each step within the above signaling pathway can also be interrogated with FDA-approved pharmaceuticals. A highlight of these studies is the demonstration of first-in-kind in vivo imaging of mitochondria respiration of any cell in the body. Future examinations of subretinal space hydration are expected to be useful for diagnosing threats to sight in aging and disease, and improving the success rate when translating treatments from bench-to-bedside.

scholarly journals Potential Treatment of Retinal Diseases with Iron Chelators

2018 ◽  
Vol 11 (4) ◽  
pp. 112 ◽  
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.

Impaired visual thresholds in hypopigmented animals

1991 ◽  
Vol 6 (6) ◽  
pp. 577-585 ◽  
Author(s):  
Grant W. Balkema ◽  
Ursula C. Dräger
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Visual Sensitivity ◽  
The Body ◽  
Melanin Pigmentation ◽  
Similar Threshold ◽  
The Mean ◽  
Single Unit Recordings ◽  
The Difference ◽  
And Function

AbstractOcular hypopigmentation is associated with neurological defects in structure and function. This paper investigates the ab/Fute visual thresholds in dark-adapted hypopigmented animals compared to their normally pigmented controls. Here we asked (1) whether the threshold elevation found in hypopigmented animals is a general consequence of the reduction in melanin content; (2) if so, which melanin components in the eye are likely to influence visual thresholds; and (3) whether similar threshold defects can be detected in orders other than rodents. By single-unit recordings from the superior colliculus, we compared incremental thresholds of normal black mice of the C57BL/6J strain to hypopigmented mutants: beige (bg/bg), pale ear (ep/ep), and albino (c2J/c2J) mice, three mutants in which melanin pigment throughout the body is affected; and Steel (Sl/Sld) and dorninant-spotting/W-mice (W/Wν), two mutants with normal pigmentation in the retinal pigment epithelium (RPE) but without any melanin in the choroid or the rest of the body. We found that all mutants had elevated thresholds that varied with the reduction in melanin. The albinos were 25 times less sensitive than black mice, pale ear mice 20 times, beige mice 11 times, and Steel and W-mice 5 times. The mean thresholds of dark-adapted black mice were 0.008 cd/m2. Recordings from rabbits showed a similar impairment of visual sensitivity: incremental thresholds were elevated 40 times in New Zealand-White albino rabbits (0.0008 cd/m2) compared to Dutch-Belted pigmented controls (0.00002 cd/m2). Previously, it has been shown that hypopigmented rats have elevated dark-adapted thresholds compared to pigmented controls (Balkema, 1988); here we show that the difference between hypopigmented rats and pigmented controls is not caused by insufficient dark adaptation or excessive variability in the results from albino mutant compared to its control.Mutations that cause a reduction of ocular melanin pigmentation, regardless of the gene mutated or the mechanism underlying the hypopigmentation, are accompanied by an elevation in visual thresholds which is roughly proportional to the reduction in melanin. Melanin both in the RPE and choroid exert an effect on visual thresholds. Like the defects in optic nerve crossing and eye movements, the effect of melanin on visual thresholds is not restricted to rodents, but is seen in other orders. The threshold impairment in hypopigmented animals cannot be explained by impaired photoprotection, but it points to another physiological action of melanin.

scholarly journals PRDX6 Protects ARPE-19 Cells from Oxidative Damage via PI3K/AKT Signaling

2015 ◽  
Vol 36 (6) ◽  
pp. 2217-2228 ◽  
Author(s):  
Xu Zha ◽  
Guojiu Wu ◽  
Xueying Zhao ◽  
Liqiong Zhou ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Damage ◽  
Blue Light ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Annexin V ◽  
Retinal Disease ◽  
Akt Signaling ◽  
The Body ◽  
H2o2 Treatment

Background/Aims: Oxidative stress that damages cells of the retinal pigment epithelium (RPE) can cause the development of hereditary retinal disease (HRD). PRDX6, which is a member of the PRDX family, is essential for removing metabolic free radicals from the body. However, the effect of PRDX6 on oxidative stress in HRD remains unknown. In this study, we sought to investigate the role of PRDX6 in oxidative stress-induced HRD in ARPE-19 cells and the molecular mechanism involved. Methods: ARPE-19 cells were used in the current study. Intracellular ROS levels were determined by flow cytometry. Lipid peroxidation was measured using a commercial MDA assay kit. Cellular variability was determined by MTT assay. Apoptosis was determined using an Annexin V-FITC Apoptosis Detection Kit. mRNA and protein expression levels were detected by real-time PCR and western blot analysis, respectively. Results: We found that H2O2 and blue light could induce significant oxidative stress damage and cell death in ARPE-19 cells. Furthermore, we found that PRDX6 levels significantly decreased after H2O2 treatment. PRDX6 overexpression protected ARPE-19 cells from H2O2- and blue light-induced oxidative damage, while PRDX6 knockdown enhanced oxidative damage in these cells. Mechanistically, we found that PRDX6 prevented oxidative damage and promoted ARPE-19 cell survival through the PI3K/AKT signaling pathway. Conclusions: Collectively, these results suggest that PRDX6 protects ARPE-19 cells from H2O2-induced oxidative stress and apoptosis and that this protection is mediated at least partially through the PI3K/AKT pathway.

scholarly journals The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa

2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Francesco Saverio Sorrentino ◽  
Claudio Bonifazzi ◽  
Paolo Perri
Keyword(s):  
Blood Flow ◽  
Retinitis Pigmentosa ◽  
Vascular System ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ocular Blood Flow ◽  
The Body ◽  
Vascular Dysregulation ◽  
Endothelin System

Retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction, which may bring about severe central vision impairment. Haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina-choroidal and in retroocular vascular system. Moreover, several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye. This might account for vasoconstriction and ischemia, typical in vascular dysregulation syndrome, which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa.

scholarly journals The Impact of miRNAs in Health and Disease of Retinal Pigment Epithelium

2021 ◽  
Vol 8 ◽  
Author(s):  
Daniela Intartaglia ◽  
Giuliana Giamundo ◽  
Ivan Conte
Keyword(s):  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Fine Tuning ◽  
Molecular Networks ◽  
Therapeutic Approaches ◽  
Pathological Conditions ◽  
Health And Disease ◽  
Non Coding Rnas ◽  
The Impact

MicroRNAs (miRNAs), a class of non-coding RNAs, are essential key players in the control of biological processes in both physiological and pathological conditions. miRNAs play important roles in fine tuning the expression of many genes, which often have roles in common molecular networks. miRNA dysregulation thus renders cells vulnerable to aberrant fluctuations in genes, resulting in degenerative diseases. The retinal pigment epithelium (RPE) is a monolayer of polarized pigmented epithelial cells that resides between the light-sensitive photoreceptors (PR) and the choriocapillaris. The demanding physiological functions of RPE cells require precise gene regulation for the maintenance of retinal homeostasis under stress conditions and the preservation of vision. Thus far, our understanding of how miRNAs function in the homeostasis and maintenance of the RPE has been poorly addressed, and advancing our knowledge is central to harnessing their potential as therapeutic agents to counteract visual impairment. This review focuses on the emerging roles of miRNAs in the function and health of the RPE and on the future exploration of miRNA-based therapeutic approaches to counteract blinding diseases.

scholarly journals Oxidative stress alters transcript localization of disease-causing genes in the retinal pigment epithelium

2021 ◽  
Author(s):  
Tadeusz J Kaczynski ◽  
Elizabeth D Au ◽  
Michael H Farkas
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Induced Pluripotent Stem Cell ◽  
The Body ◽  
Age Related Macular Degeneration ◽  
Nuclear Retention ◽  
Age Related

Nuclear retention is a mechanism whereby RNA transcripts are held in the nucleus to maintain a proper nuclear-to-cytoplasmic balance or as a stockpile for use in responding to stimuli. Many mechanisms are employed to determine whether transcripts are retained or exported to the cytoplasm, though the extent to which tissue- or cell-type, stressors, or disease pathogenesis affect this process remains unclear. As the most biochemically active tissue in the body, the retina must mitigate endogenous and exogenous stressors to maintain cell health and tissue function. Oxidative stress, believed to contribute to the pathogenesis, or progression, of age-related macular degeneration (AMD) and inherited retinal dystrophies (IRDs), is produced both internally from biochemical processes, as well as externally from environmental insult. To evaluate the effect of oxidative stress on transcript localization in the retinal pigment epithelium (RPE), we performed poly-A RNA sequencing on nuclear and cytoplasmic fractions from induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells exposed to hydrogen peroxide, as well as untreated controls. Under normal conditions, the number of mRNA transcripts retained in the nucleus exceeded that found in studies of other tissues. Further, the nuclear-to-cytoplasmic ratio of transcripts is altered following oxidative stress, as is the retention of genes associated with AMD, IRDs, and those important for RPE physiology. These results provide a retention catalog of all expressed mRNA in iPSC-RPE under normal conditions and after exposure to hydrogen peroxide, offering insight into one of the potential roles oxidative stress plays in the progression of visual disorders.

scholarly journals Retinal Pigment Epithelium Replacement Therapy for Age-Related Macular Degeneration: Are We There Yet?

2020 ◽  
Vol 60 (1) ◽  
pp. 553-572 ◽  
Author(s):  
Ruchi Sharma ◽  
Devika Bose ◽  
Arvydas Maminishkis ◽  
Kapil Bharti
Keyword(s):  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Primary Outcome ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Retinal Photoreceptors ◽  
Rpe Transplantation ◽  
Potential Therapeutics

Pluripotent stem cells (PSCs) are a potential replacement tissue source for degenerative diseases. Age-related macular degeneration (AMD) is a blinding disease triggered by degeneration of the retinal pigment epithelium (RPE), a monolayer tissue that functionally supports retinal photoreceptors. Recently published clinical and preclinical studies have tested PSC-derived RPE as a potential treatment for AMD. Multiple approaches have been used to manufacture RPE cells, to validate them functionally, to confirm their safety profile, and to deliver them to patients either as suspension or as a monolayer patch. Since most of these studies are at an early regulatory approval stage, the primary outcome has been to determine the safety of RPE transplants in patients. However, preliminary signs of efficacy were observed in a few patients. Here, we review the current progress in the PSC-derived RPE transplantation field and provide a comparative assessment of various approaches under development as potential therapeutics for AMD.

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