Tribbles Homolog 3 Mediates the Development and Progression of Diabetic Retinopathy

The current understanding of molecular pathogenesis of diabetic retinopathy does not provide a mechanistic link between early molecular changes and the subsequent progression of the disease. In this study, we found that human diabetic retinas overexpressed TRIB3 and investigated the role of TRIB3 in diabetic retinal pathobiology in mice. We discovered that TRIB3 controlled major molecular events in early diabetic retinas via HIF1α-mediated regulation of retinal glucose flux, reprograming cellular metabolism, and governing inflammatory gene expression. These early molecular events further defined the development of neurovascular deficit observed in mice with diabetic retinopathy. TRIB3 ablation in STZ-induced mouse model led to significant RGC survival and functional restoration accompanied by a dramatic reduction in pericyte loss and acellular capillary formation. Under hypoxic conditions, TRIB3 contributed to advanced proliferative stages by significant upregulation of GFAP and VEGF expression, thus controlling gliosis and aberrant vascularization in OIR mouse retinas. Overall, our data reveal that TRIB3 is a master regulator of diabetic retinal pathophysiology that may accelerate the onset and progression of diabetic retinopathy to proliferative stages in humans and present TRIB3 as a potentially novel therapeutic target for diabetic retinopathy.

Download Full-text

SENP1-Mediated Desumoylation of DBC1 Inhibits Apoptosis Induced by High Glucose in Bovine Retinal Pericytes

Journal of Ophthalmology ◽

10.1155/2016/6392658 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11

Author(s):

Jian Gao ◽

Xia Chen ◽

Qing Gu ◽

Xiaoxiao Liu ◽

Xun Xu

Keyword(s):

Diabetic Retinopathy ◽

High Glucose ◽

Molecular Mechanisms ◽

Characteristic Change ◽

High Concentration ◽

Retinal Pericytes ◽

Specific Protease ◽

Induced Apoptosis ◽

Pericyte Loss

Pericyte loss is an early characteristic change in diabetic retinopathy, but its precise molecular mechanisms have not been elucidated. This study investigated the role of SENP1 in pericyte loss in diabetic retinopathy. We demonstrated that a high concentration of glucose inhibited the expression of the Sentrin/SUMO-specific protease 1 (SENP1), which resulted in an increase in DBC1 sumoylation in bovine retinal pericytes (BRPCs). Furthermore, SENP1 overexpression attenuated hyperemia-induced apoptosis of BPRCs, and SENP1 knockdown aggravated this effect. We also provide evidence that DBC1 sumoylation/desumoylation is involved in the SENP1-regulated apoptosis of BRPCs under high glucose conditions. Understanding the role of SENP1 in the pathogenesis of high glucose induced pericyte loss could help elucidate important targets for future pharmacological interventions.

Download Full-text

Tenilsetam prevents early diabetic retinopathy without correcting pericyte loss

Thrombosis and Haemostasis ◽

10.1160/th05-11-0725 ◽

2006 ◽

Vol 95 (04) ◽

pp. 689-695 ◽

Cited By ~ 9

Author(s):

Jennifer Hoffmann ◽

Alex Alt ◽

Jihong Lin ◽

Günther Lochnit ◽

Uwe Schubert ◽

...

Keyword(s):

Endothelial Cells ◽

Diabetic Retinopathy ◽

Endothelial Cell ◽

Vegf Expression ◽

Endothelial Proliferation ◽

High Doses ◽

Acellular Capillaries ◽

Pericyte Loss ◽

The Impact

SummaryHyperglycemia-induced mitochondrial overproduction of reactive oxygen species leads to the activation of different biochemical pathways involved in endothelial damage of the diabetic retina. Tenilsetam [(±)-3-(2-thienyl)-2-piperazinone] is a dicarbonyl scavenger in the millimolar range anda transition metal ion chelator in the micromolar range. We tested its effect on experimental diabetic retinopathy, and on endothelial cell characteristics in vitro. Streptozotocin diabetic male Wistar rats (60 mg/ kg BW) received 50 mg/kg BW tenilsetam (D-T) for 36 weeks, or no treatment (D).The impact of tenilsetam (0–30 mM) on endothelial proliferation, apoptosis, sprouting, cytokine-induced leucocyte-endothelial interaction, and VEGF expression was tested in vitro.Tenilsetam did not affect glycemic control or body weight in diabetic animals. The 3.7 fold increase in acellular capillaries in diabetic rats [p<0.001 vs. non-diabetic controls (N)] was reduced by 70% (p<0.001) through treatment, but pericyte loss (D vs. N –33%; p<0.001) remained unaffected. In vitro, tenilsetam inhibited endothelial proliferation at lower doses, while inducing apoptosis at high doses. Leucocyte adhesion was only inhibited at high doses. Sprouting angiogenesis of bovine retinal endothelial cells was promoted at lower doses (≤ 10 mM). At micromolar concentrations, endothelial VEGF expression was upregulated by 100%. Long-term treatment with the AGEinhibitor and iron-chelating compound tenilsetam inhibits the formation of acellular capillaries without correcting pericyte loss. The compound has dose-dependent effects on endothelial cell function. These data suggest that, independent of known properties, tenilsetam shows important rescue functions on endothelial cells which could be useful for the treatment of early diabetic retinopathy.

Download Full-text

Pericyte Bridges in Homeostasis and Hyperglycemia: Reconsidering Pericyte Dropout and Microvascular Structures

10.1101/704007 ◽

2019 ◽

Cited By ~ 1

Author(s):

Bruce A. Corliss ◽

H. Clifton Ray ◽

Richard Doty ◽

Corbin Mathews ◽

Natasha Sheybani ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Basement Membrane ◽

In Vivo Imaging ◽

Diabetic Patients ◽

Cell Type ◽

A Cell ◽

Acellular Capillaries ◽

Pericyte Loss

AbstractDiabetic retinopathy threatens the vision of a third of diabetic patients. Progression of the disease is attributed to the dropout of pericytes, a cell type that enwraps and stabilizes the microvasculature. In tandem with this presumptive pericyte dropout, there is enriched formation of structures assumed to be remnants of collapsed or regressed vessels, previously classified as acellular capillaries, string vessels, and basement membrane bridges. Instead of endothelial cells, we show that pericytes colocalize with basement membrane bridges, and both bridging structures are enriched by cell-specific knockout of KLF4 and reversibly enriched with elevation of Ang-2, PDGF-BB, and blood sugar. Our data suggests that pericyte counts from retinal digests have misclassified pericyte bridges as endothelial structures and have exaggerated the role of pericyte loss in DR progression. In vivo imaging of corneal limbal vessels demonstrates pericyte migration off-vessel, implicating pericyte movement in formation of pericyte bridges and pathogenesis of diabetic retinopathy.

Download Full-text

Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy

Diabetes ◽

10.2337/diabetes.44.6.603 ◽

1995 ◽

Vol 44 (6) ◽

pp. 603-607 ◽

Cited By ~ 52

Author(s):

E. M. Kohner ◽

V. Patel ◽

S. M. Rassam

Keyword(s):

Blood Flow ◽

Diabetic Retinopathy

Download Full-text

Faculty Opinions recommendation of Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.11512.467521 ◽

2006 ◽

Author(s):

Helena Tlaskalova-Hogenova

Keyword(s):

Gene Expression ◽

Immune Response ◽

Celiac Disease ◽

Intestinal Permeability ◽

Innate Immune Response ◽

Innate Immune ◽

Murine Macrophage ◽

Inflammatory Gene Expression ◽

Stimulation Of

Download Full-text

The Level of Cytokines in the Vitreous Body of Severe Proliferative Diabetic Retinopathy Patients Undergoing Posterior Vitrectomy

Current Pharmaceutical Design ◽

10.2174/1381612824666180926110704 ◽

2018 ◽

Vol 24 (27) ◽

pp. 3276-3281 ◽

Cited By ~ 3

Author(s):

Dorota Raczyńska ◽

Katarzyna A. Lisowska ◽

Krzysztof Pietruczuk ◽

Joanna Borucka ◽

Mateusz Ślizień ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Proliferative Diabetic Retinopathy ◽

Vitreous Body ◽

Control Group ◽

Slit Lamp ◽

Corrected Visual Acuity ◽

Cytokine Levels ◽

Pars Plana ◽

Eye Examination

Objective: The objective of the study was to compare cytokine levels in the vitreous body of patients with proliferative diabetic retinopathy (PDR) undergoing posterior vitrectomy. Patients and methods: The study included 39 patients (39 eyes) undergoing pars plana vitrectomy (PPV). Patients were divided into three groups: patients with proliferative diabetic retinopathy (PDR) without aflibercept injection prior to the surgery, PDR patients administered aflibercept injection prior to the surgery, and patients without diabetes mellitus (control group). All patients underwent a comprehensive eye examination one day before and 3 weeks after the surgery, including measurements of: best-corrected visual acuity (BVCA) and intraocular pressure (IOP), slit-lamp examination and spectral domain optical coherence tomography (SOCT). Concentrations of cytokines: IL-6, IL-8, IL-12p70, TNF, IL-10, IL-1β were measured in the vitreous body of patients with BD™ Cytometric Bead Array (CBA) Human Inflammatory Cytokines Kit. Results: PDR patients who received pretreatment with aflibercept injection showed significantly lower concentrations of IL-12p70, TNF, IL-10 and IL-1β in the vitreous body compared to the control group. Meanwhile, patients without prior aflibercept injection had a significantly higher concentration of IL-8. There was also a significant positive correlation between IOP before PPV and IL-8 concentration in both PDR patients’ groups. Conclusion: Findings of our study suggest an important role of IL-8 in the development of severe PDR. Aflibercept administration on the day before elective vitrectomy facilitated the surgery.

Download Full-text

Role of Endothelin in Diabetic Retinopathy

Current Vascular Pharmacology ◽

10.2174/1570161033476600 ◽

2003 ◽

Vol 1 (3) ◽

pp. 243-250 ◽

Cited By ~ 15

Author(s):

Hing-Chung Lam ◽

Jenn-Kuen Lee ◽

Chih-Chen Lu ◽

Chih-Hsun Chu ◽

Ming-Ju Chuang ◽

...

Keyword(s):

Diabetic Retinopathy

Download Full-text

Reduced Levels of Drp1 Protect against Development of Retinal Vascular Lesions in Diabetic Retinopathy

Cells ◽

10.3390/cells10061379 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1379

Author(s):

Dongjoon Kim ◽

Hiromi Sesaki ◽

Sayon Roy

Keyword(s):

Diabetic Retinopathy ◽

Cell Loss ◽

Vascular Lesions ◽

Protective Effects ◽

Diabetic Mice ◽

Wild Type ◽

Apoptotic Genes ◽

Retinal Vascular Lesions ◽

Acellular Capillaries ◽

Pericyte Loss

High glucose (HG)-induced Drp1 overexpression contributes to mitochondrial dysfunction and promotes apoptosis in retinal endothelial cells. However, it is unknown whether inhibiting Drp1 overexpression protects against the development of retinal vascular cell loss in diabetes. To investigate whether reduced Drp1 level is protective against diabetes-induced retinal vascular lesions, four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Drp1+/− mice, and STZ-induced diabetic Drp1+/− mice were examined after 16 weeks of diabetes. Western Blot analysis indicated a significant increase in Drp1 expression in the diabetic retinas compared to those of WT mice; retinas of diabetic Drp1+/− mice showed reduced Drp1 level compared to those of diabetic mice. A significant increase in the number of acellular capillaries (AC) and pericyte loss (PL) was observed in the retinas of diabetic mice compared to those of the WT control mice. Importantly, a significant decrease in the number of AC and PL was observed in retinas of diabetic Drp1+/− mice compared to those of diabetic mice concomitant with increased expression of pro-apoptotic genes, Bax, cleaved PARP, and increased cleaved caspase-3 activity. Preventing diabetes-induced Drp1 overexpression may have protective effects against the development of vascular lesions, characteristic of diabetic retinopathy.

Download Full-text

Coenzyme Q10 and Immune Function: An Overview

Antioxidants ◽

10.3390/antiox10050759 ◽

2021 ◽

Vol 10 (5) ◽

pp. 759

Author(s):

David Mantle ◽

Robert A. Heaton ◽

Iain P. Hargreaves

Keyword(s):

Immune System ◽

Immune Function ◽

Coenzyme Q10 ◽

Mitochondrial Respiratory Chain ◽

Inflammatory Gene Expression ◽

Optimal Functioning ◽

Human Immune ◽

Coq10 Supplementation ◽

Lipid Soluble Antioxidant

Coenzyme Q10 (CoQ10) has a number of important roles in the cell that are required for optimal functioning of the immune system. These include its essential role as an electron carrier in the mitochondrial respiratory chain, enabling the process of oxidative phosphorylation to occur with the concomitant production of ATP, together with its role as a potential lipid-soluble antioxidant, protecting the cell against free radical-induced oxidation. Furthermore, CoQ10 has also been reported to have an anti-inflammatory role via its ability to repress inflammatory gene expression. Recently, CoQ10 has also been reported to play an important function within the lysosome, an organelle central to the immune response. In view of the differing roles CoQ10 plays in the immune system, together with the reported ability of CoQ10 supplementation to improve the functioning of this system, the aim of this article is to review the current literature available on both the role of CoQ10 in human immune function and the effect of CoQ10 supplementation on this system.

Download Full-text