The neuroscience of diabetic retinopathy

Visual Neuroscience ◽

10.1017/s0952523820000115 ◽

2021 ◽

Vol 38 ◽

Author(s):

David A. Antonetti

Keyword(s):

Diabetic Retinopathy ◽

Molecular Basis ◽

Ganglion Cells ◽

Neurovascular Unit ◽

Microvascular Disease ◽

Neural Tissue ◽

Intimate Relationship ◽

Cellular Communications ◽

Cellular Environment ◽

Tissue Form

Abstract Diabetic retinopathy remains a leading cause of blindness despite recent advance in therapies. Traditionally, this complication of diabetes was viewed predominantly as a microvascular disease but research has pointed to alterations in ganglion cells, glia, microglia, and photoreceptors as well, often occurring without obvious vascular damage. In neural tissue, the microvasculature and neural tissue form an intimate relationship with the neural tissue providing signaling cues for the vessels to form a distinct barrier that helps to maintain the proper neuronal environment for synaptic signaling. This relationship has been termed the neurovascular unit (NVU). Research is now focused on understanding the cellular and molecular basis of the neurovascular unit and how diabetes alters the normal cellular communications and disrupts the cellular environment contributing to loss of vision in diabetes.

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Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease

Antioxidants ◽

10.3390/antiox9100905 ◽

2020 ◽

Vol 9 (10) ◽

pp. 905 ◽

Cited By ~ 4

Author(s):

David J. Miller ◽

M. Ariel Cascio ◽

Mariana G. Rosca

Keyword(s):

Diabetic Retinopathy ◽

Vision Loss ◽

Neurovascular Unit ◽

Microvascular Disease ◽

Retinal Disease ◽

Neural Retina ◽

Vascular Pathology ◽

Future Research ◽

Substrate Selection ◽

Working Age

Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.

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Crosstalk in the Retinal Neurovascular Unit – Lessons for the Diabetic Retina

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0032-1304571 ◽

2012 ◽

Vol 120 (04) ◽

pp. 199-201 ◽

Cited By ~ 17

Author(s):

Y. Feng ◽

S. Busch ◽

N. Gretz ◽

S. Hoffmann ◽

H.-P. Hammes

Keyword(s):

Innate Immunity ◽

Diabetic Retinopathy ◽

Animal Models ◽

Ganglion Cells ◽

Neurovascular Unit ◽

Retinal Diseases ◽

Diabetic Retina ◽

Retinal Thinning ◽

The Impact ◽

The Complement System

AbstractDiabetic retinopathy shares important features with neurodegenerative retinal diseases, including loss of ganglion cells and retinal thinning. The impact on vasoregression and subsequent ischemia-driven changes such as macular edema and proliferative retinopathy are not established. Studies using adult neurodegenerative animal models such as the transgenic TGR(CMV-PKD2(1/703)HA) rat imply early activation of the innate immunity system and the complement system as well as microglia playing a role in the damage of the retinal neurovascular unit.

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Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy

Pharmaceutics ◽

10.3390/pharmaceutics13081320 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1320

Author(s):

Rafael Simó ◽

Olga Simó-Servat ◽

Patricia Bogdanov ◽

Cristina Hernández

Keyword(s):

Diabetic Retinopathy ◽

Essential Role ◽

Neurovascular Unit ◽

Microvascular Disease ◽

Diabetic Complication ◽

Experimental Models ◽

Therapeutic Approaches ◽

Primary Event ◽

Early Stages ◽

Neuroprotective Treatment

The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.

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Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

Eye and Vision ◽

10.1186/s40662-021-00239-1 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Shen Nian ◽

Amy C. Y. Lo ◽

Yajing Mi ◽

Kai Ren ◽

Di Yang

Keyword(s):

Diabetic Retinopathy ◽

Early Stage ◽

Neurovascular Unit ◽

Microvascular Disease ◽

Industrialized Countries ◽

Novel Treatments ◽

Microvascular Changes ◽

Working Age ◽

Retinal Neurodegeneration ◽

The Common

AbstractDiabetic retinopathy (DR), one of the common complications of diabetes, is the leading cause of visual loss in working-age individuals in many industrialized countries. It has been traditionally regarded as a purely microvascular disease in the retina. However, an increasing number of studies have shown that DR is a complex neurovascular disorder that affects not only vascular structure but also neural tissue of the retina. Deterioration of neural retina could precede microvascular abnormalities in the DR, leading to microvascular changes. Furthermore, disruption of interactions among neurons, vascular cells, glia and local immune cells, which collectively form the neurovascular unit, is considered to be associated with the progression of DR early on in the disease. Therefore, it makes sense to develop new therapeutic strategies to prevent or reverse retinal neurodegeneration, neuroinflammation and impaired cell-cell interactions of the neurovascular unit in early stage DR. Here, we present current perspectives on the pathophysiology of DR as a neurovascular disease, especially at the early stage. Potential novel treatments for preventing or reversing neurovascular injuries in DR are discussed as well.

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

Scientific Reports ◽

10.1038/s41598-021-88698-3 ◽

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.

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Retinal microglia polarization in diabetic retinopathy

Visual Neuroscience ◽

10.1017/s0952523821000031 ◽

2021 ◽

Vol 38 ◽

Author(s):

Xin Li ◽

Zi-Wei Yu ◽

Hui-Yao Li ◽

Yue Yuan ◽

Xin-Yuan Gao ◽

...

Keyword(s):

Central Nervous System ◽

Diabetic Retinopathy ◽

Cytokine Production ◽

Immune Cell ◽

Microvascular Disease ◽

Retinal Diseases ◽

Microglia Polarization ◽

Retinal Microglia ◽

The Central Nervous System ◽

Retinal Neurodegeneration

Abstract Microglia, the main immune cell of the central nervous system (CNS), categorized into M1-like phenotype and M2-like phenotype, play important roles in phagocytosis, cell migration, antigen presentation, and cytokine production. As a part of CNS, retinal microglial cells (RMC) play an important role in retinal diseases. Diabetic retinopathy (DR) is one of the most common complications of diabetes. Recent studies have demonstrated that DR is not only a microvascular disease but also retinal neurodegeneration. RMC was regarded as a central role in neurodegeneration and neuroinflammation. Therefore, in this review, we will discuss RMC polarization and its possible regulatory factors in early DR, which will provide new targets and insights for early intervention of DR.

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A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

Nutrients ◽

10.3390/nu13072441 ◽

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.

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Dynamic Expression of HDAC3 in db/db Mouse RGCs and Its Relationship with Apoptosis and Autophagy

Journal of Diabetes Research ◽

10.1155/2020/6086780 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuhong Fu ◽

Ying Wang ◽

Xinyuan Gao ◽

Huiyao Li ◽

Yue Yuan

Keyword(s):

Diabetic Retinopathy ◽

Ganglion Cell ◽

Retinal Ganglion Cells ◽

Retinal Ganglion Cell ◽

Ganglion Cells ◽

Control Group ◽

Diabetic Patients ◽

Retinal Ganglion ◽

Glucose Levels ◽

Dynamic Expression

Background. Diabetic retinopathy (DR) is a severe complication of diabetes mellitus. DR is considered as a neurovascular disease. Retinal ganglion cell (RGC) loss plays an important role in the vision function disorder of diabetic patients. Histone deacetylase3 (HDAC3) is closely related to injury repair and nerve regeneration. The correlation between HDAC3 and retinal ganglion cells in diabetic retinopathy is still unclear yet. Methods. To investigate the chronological sequence of the abnormalities of retinal ganglion cells in diabetic retinopathy, we choose 15 male db/db mice (aged 8 weeks, 12 weeks, 16 weeks, 18 weeks, and 25 weeks; each group had 3 mice) as diabetic groups and 3 male db/m mice (aged 8 weeks) as the control group. In this study, we examined the morphological and immunohistochemical changes of HDAC3, Caspase3, and LC3B in a sequential manner by characterizing the process of retinal ganglion cell variation. Results. Blood glucose levels and body weights of db/db mice were significantly higher than that of the control group, P<0.01. Compared with the control group, the number of retinal ganglion cells decreased with the duration of disease increasing. HDAC3 expression gradually increased in RGCs of db/db mice. Caspase3 expression gradually accelerated in RGCs of db/db mice. LC3B expression dynamically changed in RGCs of db/db mice. HDAC3 was positively correlated with Caspase3 expression (r=0.7424), P<0.01. HDAC3 was positively correlated with LC3B expression (r=0.7336), P<0.01. Discussion. We clarified the dynamic expression changes of HDAC3, Caspase3, and LC3B in retinal ganglion cells of db/db mice. Our results suggest the HDAC3 expression has a positive correlation with apoptosis and autophagy.

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Retinal Neuropathy in IGT Stage of OLETF Rats: Another Characteristic Change of Diabetic Retinopathy

Journal of Diabetes Research ◽

10.1155/2021/3181347 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Zhenhong Guo ◽

Xiaoyue Sun ◽

Juhong Yang ◽

Jinlan Xie ◽

Feifei Zhong ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Glucose Tolerance ◽

Ganglion Cells ◽

Normal Glucose Tolerance ◽

Characteristic Change ◽

Retinal Ganglion ◽

Oletf Rats ◽

Significant Damage ◽

Normal Glucose ◽

Retinal Structure

Aims. We investigated the changes of retinal structure in normal glucose tolerance (NGT), impaired glucose tolerance (IGT), diabetes mellitus (DM), and diabetic kidney disease (DKD) stages in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods. We assigned OLETF rats to four groups based on their OGTT results and 24 h urinary microalbumin (24 h UMA) levels: NGT, IGT, DM, and DKD groups. We observed the structural and the corresponding pathological changes and quantified the expression of HIF-1α, iNOS, NF-κB, VEGF, ICAM-1, and occludin in the retina. Results. Significant damage to the retinal structure, especially in retinal ganglion cells (RGCs), was observed in the IGT stage. The expression of HIF-1α, iNOS, NF-κB, VEGF, and ICAM-1 was significantly upregulated, while that of occludin was downregulated. Conclusion. Significant retinal neuropathy occurs in the IGT stage. Inflammation and hypoxia may damage the blood retina barrier (BRB), leading to diabetic retinopathy.

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