scholarly journals Mineralocorticoid receptor pathway and its antagonism in a model of diabetic retinopathy

2021 ◽  
Author(s):  
Min Zhao ◽  
Emmanuelle Gelize ◽  
Rinath Levy ◽  
Alexandre Moulin ◽  
Frédéric Azan ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Mineralocorticoid Receptor ◽  
Vision Loss ◽  
Therapeutic Option ◽  
Lipocalin 2 ◽  
Gk Rats ◽  
Diabetic Retina ◽  
Pathway Activation ◽  
Genes Encoding ◽  
Galectin 3

<p>Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and, that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetic complications regulated by MR are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage and retinal edema through the up-regulation of genes encoding proteins known to intervene in vascular permeability such as <i>Hey1, Vldlr</i>, <i>Pten</i>, <i>Slc7a1, Tjp1, Dlg1 and Sesn2 </i>but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.</p>

scholarly journals Mineralocorticoid receptor pathway and its antagonism in a model of diabetic retinopathy

2021 ◽  
Author(s):  
Min Zhao ◽  
Emmanuelle Gelize ◽  
Rinath Levy ◽  
Alexandre Moulin ◽  
Frédéric Azan ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Mineralocorticoid Receptor ◽  
Vision Loss ◽  
Therapeutic Option ◽  
Lipocalin 2 ◽  
Gk Rats ◽  
Diabetic Retina ◽  
Pathway Activation ◽  
Genes Encoding ◽  
Galectin 3

<p>Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and, that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetic complications regulated by MR are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage and retinal edema through the up-regulation of genes encoding proteins known to intervene in vascular permeability such as <i>Hey1, Vldlr</i>, <i>Pten</i>, <i>Slc7a1, Tjp1, Dlg1 and Sesn2 </i>but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy.</p>

scholarly journals Acrolein: A Potential Mediator of Oxidative Damage in Diabetic Retinopathy

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1579 ◽  
Author(s):  
Moaddey Alfarhan ◽  
Eissa Jafari ◽  
S. Priya Narayanan
Keyword(s):  
Diabetic Retinopathy ◽  
Oxidative Damage ◽  
Vision Loss ◽  
Critical Role ◽  
Neurovascular Unit ◽  
Antioxidant Properties ◽  
Therapeutic Interventions ◽  
Diabetic Retina ◽  
Working Age ◽  
The Impact

Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults. Extensive evidences have documented that oxidative stress mediates a critical role in the pathogenesis of DR. Acrolein, a product of polyamines oxidation and lipid peroxidation, has been demonstrated to be involved in the pathogenesis of various human diseases. Acrolein’s harmful effects are mediated through multiple mechanisms, including DNA damage, inflammation, ROS formation, protein adduction, membrane disruption, endoplasmic reticulum stress, and mitochondrial dysfunction. Recent investigations have reported the involvement of acrolein in the pathogenesis of DR. These studies have shown a detrimental effect of acrolein on the retinal neurovascular unit under diabetic conditions. The current review summarizes the existing literature on the sources of acrolein, the impact of acrolein in the generation of oxidative damage in the diabetic retina, and the mechanisms of acrolein action in the pathogenesis of DR. The possible therapeutic interventions such as the use of polyamine oxidase inhibitors, agents with antioxidant properties, and acrolein scavengers to reduce acrolein toxicity are also discussed.

scholarly journals The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy

2021 ◽  
Vol 11 ◽  
Author(s):  
Josy Augustine ◽  
Evan P. Troendle ◽  
Peter Barabas ◽  
Corey A. McAleese ◽  
Thomas Friedel ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Current Knowledge ◽  
Microvascular Complications ◽  
Diabetic Complication ◽  
Diabetic Retina ◽  
Detoxification Systems ◽  
Lipid Aldehydes

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

scholarly journals Analysis of Lipid Peroxidation by UPLC-MS/MS and Retinoprotective Effects of the Natural Polyphenol Pterostilbene

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 168
Author(s):  
Isabel Torres-Cuevas ◽  
Iván Millán ◽  
Miguel Asensi ◽  
Máximo Vento ◽  
Camille Oger ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Diabetic Retinopathy ◽  
Redox Homeostasis ◽  
Ultra Performance Liquid Chromatography ◽  
Protective Effects ◽  
Diabetic Retina ◽  
Key Factor ◽  
Adrenic Acid ◽  
Diabetic Rabbits ◽  
High Level

The loss of redox homeostasis induced by hyperglycemia is an early sign and key factor in the development of diabetic retinopathy. Due to the high level of long-chain polyunsaturated fatty acids, diabetic retina is highly susceptible to lipid peroxidation, source of pathophysiological alterations in diabetic retinopathy. Previous studies have shown that pterostilbene, a natural antioxidant polyphenol, is an effective therapy against diabetic retinopathy development, although its protective effects on lipid peroxidation are not well known. Plasma, urine and retinas from diabetic rabbits, control and diabetic rabbits treated daily with pterostilbene were analyzed. Lipid peroxidation was evaluated through the determination of derivatives from arachidonic, adrenic and docosahexaenoic acids by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Diabetes increased lipid peroxidation in retina, plasma and urine samples and pterostilbene treatment restored control values, showing its ability to prevent early and main alterations in the development of diabetic retinopathy. Through our study, we are able to propose the use of a derivative of adrenic acid, 17(RS)-10-epi-SC-Δ15-11-dihomo-IsoF, for the first time, as a suitable biomarker of diabetic retinopathy in plasmas or urine.

scholarly journals Visual Cortex Transcranial Direct Current Stimulation for Proliferative Diabetic Retinopathy Patients: A Double-Blinded Randomized Exploratory Trial

2021 ◽  
Vol 11 (2) ◽  
pp. 270
Author(s):  
Angelito Braulio F. de Venecia ◽  
Shane M. Fresnoza
Keyword(s):  
Diabetic Retinopathy ◽  
Visual Cortex ◽  
Proliferative Diabetic Retinopathy ◽  
Direct Current ◽  
Transcranial Direct Current Stimulation ◽  
Vision Loss ◽  
Sham Stimulation ◽  
Direct Current Stimulation ◽  
Residual Vision ◽  
Cathodal Tdcs

Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes. PDR-related retinal hemorrhages often lead to severe vision loss. The main goals of management are to prevent visual impairment progression and improve residual vision. We explored the potential of transcranial direct current stimulation (tDCS) to enhance residual vision. tDCS applied to the primary visual cortex (V1) may improve visual input processing from PDR patients’ retinas. Eleven PDR patients received cathodal tDCS stimulation of V1 (1 mA for 10 min), and another eleven patients received sham stimulation (1 mA for 30 s). Visual acuity (logarithm of the minimum angle of resolution (LogMAR) scores) and number acuity (reaction times (RTs) and accuracy rates (ARs)) were measured before and immediately after stimulation. The LogMAR scores and the RTs of patients who received cathodal tDCS decreased significantly after stimulation. Cathodal tDCS has no significant effect on ARs. There were no significant changes in the LogMAR scores, RTs, and ARs of PDR patients who received sham stimulation. The results are compatible with our proposal that neuronal noise aggravates impaired visual function in PDR. The therapeutic effect indicates the potential of tDCS as a safe and effective vision rehabilitation tool for PDR patients.

scholarly journals Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1683
Author(s):  
Milagros Mateos-Olivares ◽  
Luis García-Onrubia ◽  
Fco. Javier Valentín-Bravo ◽  
Rogelio González-Sarmiento ◽  
Maribel Lopez-Galvez ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Macular Oedema ◽  
Standard Therapy ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Rho Kinase ◽  
Diabetic Macular Oedema ◽  
New Drugs ◽  
Anti Vegf

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

scholarly journals Plasma microRNA signature associated with retinopathy in patients with type 2 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donato Santovito ◽  
Lisa Toto ◽  
Velia De Nardis ◽  
Pamela Marcantonio ◽  
Rossella D’Aloisio ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Vision Loss ◽  
External Validation ◽  
Diabetic Patients ◽  
Disease Biomarkers ◽  
Response To Stress ◽  
Severity Of The Disease ◽  
Plasma Microrna

AbstractDiabetic retinopathy (DR) is a leading cause of vision loss and disability. Effective management of DR depends on prompt treatment and would benefit from biomarkers for screening and pre-symptomatic detection of retinopathy in diabetic patients. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression which are released in the bloodstream and may serve as biomarkers. Little is known on circulating miRNAs in patients with type 2 diabetes (T2DM) and DR. Here we show that DR is associated with higher circulating miR-25-3p (P = 0.004) and miR-320b (P = 0.011) and lower levels of miR-495-3p (P < 0.001) in a cohort of patients with T2DM with DR (n = 20), compared with diabetic subjects without DR (n = 10) and healthy individuals (n = 10). These associations persisted significant after adjustment for age, gender, and HbA1c. The circulating levels of these miRNAs correlated with severity of the disease and their concomitant evaluation showed high accuracy for identifying DR (AUROC = 0.93; P < 0.001). Gene ontology analysis of validated targets revealed enrichment in pathways such as regulation of metabolic process (P = 1.5 × 10–20), of cell response to stress (P = 1.9 × 10–14), and development of blood vessels (P = 2.7 × 10–14). Pending external validation, we anticipate that these miRNAs may serve as putative disease biomarkers and highlight novel molecular targets for improving care of patients with diabetic retinopathy.

scholarly journals A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2441
Author(s):  
Drake W. Lem ◽  
Dennis L. Gierhart ◽  
Pinakin Gunvant Davey
Keyword(s):  
Diabetic Retinopathy ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Microvascular Disease ◽  
Age Related Macular Degeneration ◽  
Cell Degeneration ◽  
Neuroprotective Effects ◽  
Age Related ◽  
Induced Changes ◽  
Dietary Carotenoid

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

An Explainable Deep Learning Ensemble Model for Robust Diagnosis of Diabetic Retinopathy Grading

2021 ◽  
Vol 17 (3s) ◽  
pp. 1-24
Author(s):  
Mohammad Shorfuzzaman ◽  
M. Shamim Hossain ◽  
Abdulmotaleb El Saddik
Keyword(s):  
Diabetic Retinopathy ◽  
Deep Learning ◽  
Vision Loss ◽  
Final Diagnosis ◽  
Learning Rate ◽  
Ensemble Model ◽  
Fundus Images ◽  
Robust Detection ◽  
Retinal Fundus Images ◽  
Retinal Fundus

Diabetic retinopathy (DR) is one of the most common causes of vision loss in people who have diabetes for a prolonged period. Convolutional neural networks (CNNs) have become increasingly popular for computer-aided DR diagnosis using retinal fundus images. While these CNNs are highly reliable, their lack of sufficient explainability prevents them from being widely used in medical practice. In this article, we propose a novel explainable deep learning ensemble model where weights from different models are fused into a single model to extract salient features from various retinal lesions found on fundus images. The extracted features are then fed to a custom classifier for the final diagnosis of DR severity level. The model is trained on an APTOS dataset containing retinal fundus images of various DR grades using a cyclical learning rates strategy with an automatic learning rate finder for decaying the learning rate to improve model accuracy. We develop an explainability approach by leveraging gradient-weighted class activation mapping and shapely adaptive explanations to highlight the areas of fundus images that are most indicative of different DR stages. This allows ophthalmologists to view our model's decision in a way that they can understand. Evaluation results using three different datasets (APTOS, MESSIDOR, IDRiD) show the effectiveness of our model, achieving superior classification rates with a high degree of precision (0.970), sensitivity (0.980), and AUC (0.978). We believe that the proposed model, which jointly offers state-of-the-art diagnosis performance and explainability, will address the black-box nature of deep CNN models in robust detection of DR grading.

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