Increased O-GlcNAcylation of NF-κB Enhances Retinal Ganglion Cell Death in Streptozotocin-induced Diabetic Retinopathy

Kim, Seong-Jae; Yoo, Woong-Sun; Choi, Mee-Young; Chung, In‐Young; Yoo, Jinyoung; Choi, Woong

doi:10.3109/02713683.2015.1006372

Cited by 46 publications

(42 citation statements)

References 39 publications

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“…An immunohistochemistry study with streptozotocin-diabetic rats showed 20% diminution in the NeuN-positive retinal ganglion cells after 4 months of diabetes [10]. A previous study showed that hyperglycemia increases O-GlcNAcylation in GCL and Inner Nuclear Layer (INL) in STZ-induced diabetic mice retinas and increased O-GlcNAcylation is associated with RGC death in diabetic retinas [11]. These studies revealed that RGC apoptosis begins soon after the onset of diabetes.…”

Section: Discussionmentioning

confidence: 76%

The Relationship between Retinal Ganglion Cell Damage with Duration of Diabetes and Diabetic Retinopathy Status

Tabakçı¹

2017

Int J Ophthalmol Clin Res

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Purpose: We determined whether Diabetes Mellitus (DM) affects the retinal Ganglion Cell-Inner Plexiform Layer (GCI-PL) thickness in patients who have no Diabetic Retinopathy (DR) or Non-Proliferative Diabetic Retinopathy (NPDR).Design: Retrospective, comparative study. Methods:Of 60 DM patients, 56 eyes with no DR (group 1) and 52 eyes with NPDR (group 2), and 104 eyes of 60 healthy subjects underwent the Ganglion Cell Analysis (GCA) using Optical Coherence Tomography (OCT). GCA algorithm was used to measure the thickness of the overall avarage, minimum, superotemporal, superior, superonasal, inferonasal, inferior, inferotemporal GCIPL. Measurements of GCIPL thickness and central macular thickness of DM patients were compared with those of age and gender matched control group. Results:The overall average, minimum, and the six sectors of GCIPL thickness measurements were significantly thinner in DM patients compared with healthy controls (p < 0.05), but there was no significant difference between groups 1 and 2 (p > 0.05). In terms of duration of diabetes and DR status, there was no statistically significant difference in GCIPL parameters while correcting for age and presence of hypertension between the groups. Conclusion:This study demonstrates a significant GCIPL thinning at all segments of the macula in DM patients than in healthy controls. In contrast, there was no significant difference between group 1 and 2 in terms of GCIPL thickness. These results confirm that DM has a neurodegenerative effect on the retina before vascular changes occur.

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Section: Discussionmentioning

confidence: 76%

The Relationship between Retinal Ganglion Cell Damage with Duration of Diabetes and Diabetic Retinopathy Status

Tabakçı¹

2017

Int J Ophthalmol Clin Res

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“…DR is a common DM-related micro-vascular complication, which alters the permeability of retinal micro-vessels and increases the adhesion of leukocytes and secretion of cytokines and chemokines, leading to progressive damage of the micro-vessels (Kim et al, 2015). Approximately one-third of DM patients presented retinal complications, including diabetic macular edema and proliferative diabetic retinopathy, both of which may lead to severe vision impairment or even blindness (Price et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

Zhao

Liu

2016

Genet. Mol. Res.

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ABSTRACT. Diabetic retinopathy (DR), a major complication of diabetes mellitus, is the leading cause of adult blindness. The Toll-like receptor (TLR) family is believed to be involved in the pathogenesis and progression of DR. Here, we investigated the expression profiles of TLR-2 and TLR-4 in retinal ganglion cells (RGCs), in an attempt to elucidate the role of these molecules in the etiology of DR. In vitro cultured RGCs were divided into control and high-glucose groups. The mRNA and protein levels of TLR-2, TLR-4, and nuclear factor (NF)-κB were detected by real-time PCR and western blotting. RGCs were further transfected with specific siRNA targeting TLR2/TLR4; the proliferation of transfected RGCs and their tumor necrosis factor (TNF)-α and interleukin (IL)-8 secretory capacity were analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and enzyme-linked immunosorbent assays (ELISA), respectively. In a high-glucose environment, TLR-2/4 expression was significantly upregulated in RGCs (while their viability decreased); additionally, NF-κB expression and secretion of TNF-α and IL-8 were significantly increased. Co-silencing of the TLR-2 and TLR-4 genes inhibited NF-κB expression and TNF-α/IL-8 secretion, while increasing the survival rate of RGCs. Therefore, a high-glucose environment can potentiate the expression of TLR-2 and TLR-4 in RGCs, activate the downstream signaling pathway, and increase the secretion of pro-inflammatory factors, thereby aggravating DR.

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“…In a streptozotocin-induced diabetic retinopathy model, increased O-GlcNAcylation of NFκB is responsible for retinal ganglion cell death [84]. Global O-GlcNAcylation was increased, together with an increase in OGT, while there is decreased expression levels of OGA in diabetes model mice compared to control [84]. This may have important implications for the programmed cell death associated with hexosamine metabolism and neurodegeneration.…”

Section: O-glcnacylation Apoptosis and Autophagymentioning

confidence: 99%

O-GlcNAcylation and neurodegeneration

Wani

Chatham

Darley‐Usmar

et al. 2017

Brain Research Bulletin

105

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O-GlcNAcylation is a dynamic form of protein glycosylation which involves the addition of β-D-N-acetylglucosamine (GlcNAc) via an O-linkage to serine or threonine residues of nuclear, cytoplasmic, mitochondrial and transmembrane proteins. The two enzymes responsible for O-GlcNAc cycling are O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA); their expression and activities in brain are age dependent. More than 1000 O-GlcNAc protein targets have been identified which play critical roles in many cellular processes. In mammalian brain, O-GlcNAc modification of Tau decreases its phosphorylation and toxicity, suggesting a neuroprotective role of pharmacological elevation of brain O-GlcNAc for Alzheimer’s disease treatment. Other observations suggest that elevating O-GlcNAc levels may decrease protein clearance or induce apoptosis. This review highlights some of the key findings regarding O-GlcNAcylation in models of neurodegenerative diseases.

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Increased O-GlcNAcylation of NF-κB Enhances Retinal Ganglion Cell Death in Streptozotocin-induced Diabetic Retinopathy

Abstract: The present data suggest that hyperglycemia increases O-GlcNAcylation in DR and that O-GlcNAcylation of the p65 subunit of NF-κB is involved in hyperglycemia-induced NF-κB activation and RGC death in DR.

Cited by 46 publications

References 39 publications

The Relationship between Retinal Ganglion Cell Damage with Duration of Diabetes and Diabetic Retinopathy Status

The Relationship between Retinal Ganglion Cell Damage with Duration of Diabetes and Diabetic Retinopathy Status

Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications

O-GlcNAcylation and neurodegeneration

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