Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model

Ran, Ruijin; Zheng, Xiaoying; Du, Liping; Zhang, Xuedong; Chen, Xiaoli; Zhu, Shirley

doi:10.18240/ijo.2016.11.09

Cited by 6 publications

(7 citation statements)

References 26 publications

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“…The integrity of tight junctions was reported to be responsible for the brain endothelial permeability [ 31 ]; thus, the loss of tight junction proteins may cause BBB disruption, leading to the various CNS diseases [ 32 – 34 ]. Especially, diabetes is emerging as a critical issue in BBB breakdown [ 35 , 36 ], suggesting that high glucose could damage the cells and attenuate the integrity of tight junction [ 37 – 39 ]. In this present study, we confirmed that high glucose activates mRNA expressions of p-53 and Bax and protein expression of cleaved PARP which indicates the activation of cell death signaling [ 35 , 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

Song

Yoon

Kim

2017

Oxidative Medicine and Cellular Longevity

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Hyperglycemia-induced stress in the brain of patients with diabetes triggers the disruption of blood-brain barrier (BBB), leading to diverse neurological diseases including stroke and dementia. Recently, the role of microRNA becomes an interest in the research for deciphering the mechanism of brain endothelial cell damage under hyperglycemia. Therefore, we investigated whether mircoRNA Let7A (miR-Let7A) controls the damage of brain endothelial (bEnd.3) cells against high glucose condition. Cell viability, cell death marker expressions (p-53, Bax, and cleaved poly ADP-ribose polymerase), the loss of tight junction proteins (ZO-1 and claudin-5), proinflammatory response (interleukin-6, tumor necrosis factor-α), inducible nitric oxide synthase, and nitrite production were confirmed using MTT, reverse transcription-PCR, quantitative-PCR, Western blotting, immunofluorescence, and Griess reagent assay. miR-Let7A overexpression significantly prevented cell death and loss of tight junction proteins and attenuated proinflammatory response and nitrite production in the bEnd.3 cells under high glucose condition. Taken together, we suggest that miR-Let7A may attenuate brain endothelial cell damage by controlling cell death signaling, loss of tight junction proteins, and proinflammatory response against high glucose stress. In the future, the manipulation of miR-Let7A may be a novel solution in controlling BBB disruption which leads to the central nervous system diseases.

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Section: Discussionmentioning

confidence: 99%

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

Song

Yoon

Kim

2017

Oxidative Medicine and Cellular Longevity

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“…HMGB1 may have a role in the alteration of BRB HMGB1 expression, which is enhanced in the retinas of diabetic rats, and BRB permeability is significantly increased [70].…”

Section: Hmgb1 and Drmentioning

confidence: 99%

The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies

et al. 2020

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High-mobility group box 1 (HMGB1) is a protein that is part of a larger family of non-histone nuclear proteins. HMGB1 is a ubiquitary protein with different isoforms, linked to numerous physiological and pathological pathways. HMGB1 is involved in cytokine and chemokine release, leukocyte activation and migration, tumorigenesis, neoangiogenesis, and the activation of several inflammatory pathways. HMGB1 is, in fact, responsible for the trigger, among others, of nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), toll-like receptor-4 (TLR-4), and vascular endothelial growth factor (VEGF) pathways. Diabetic retinopathy (DR) is a common complication of diabetes mellitus (DM) that is rapidly growing in number. DR is an inflammatory disease caused by hyperglycemia, which determines the accumulation of oxidative stress and cell damage, which ultimately leads to hypoxia and neovascularization. Recent evidence has shown that hyperglycemia is responsible for the hyperexpression of HMGB1. This protein activates numerous pathways that cause the development of DR, and HMGB1 levels are constantly increased in diabetic retinas in both proliferative and non-proliferative stages of the disease. Several molecules, such as glycyrrhizin (GA), have proven effective in reducing diabetic damage to the retina through the inhibition of HMGB1. The main focus of this review is the growing amount of evidence linking HMGB1 and DR as well as the new therapeutic strategies involving this protein.

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“…At that time, increased BRB permeability, assessed using albumin-bound dye, was noted; BBB permeability was also increased, but to a lesser extent that was not significant. However, both tissues displayed histological damage and increased protein levels of the proinflammatory cytokine ICAM-1 (8). These results suggest similar pathology, but different time course, to hyperglycemic insult in retina and brain.…”

Section: Introductionmentioning

confidence: 69%

“…Given these similar mechanisms, it has been suggested that changes in retinal vasculature may be indicative of changes in brain vasculature and/or memory i m p a i r m e n t (5 -7 ) . A di r e c t c om pa ri so n be t we e n hyperglycemia-induced retinal changes and brain changes was performed in a Type 2 diabetes rodent model (8). In this study, BRB and BBB permeability was assessed 16 weeks (4 months) after inducing Type 2 diabetes with a high fat diet followed by streptozotocin injection.…”

Section: Introductionmentioning

confidence: 99%

Time dependent effects of prolonged hyperglycemia in zebrafish brain and retina

Rowe¹,

Delbridge‐Perry²,

Bonan³

et al. 2022

Front. Ophthalmol.

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Prolonged hyperglycemia causes long-term vision complications and an increased risk of cognitive deficits. High blood sugar also confers an osmotic load/stress to cells. We assessed behavioral and neurochemical changes in zebrafish brain and retina following prolonged hyperglycemia for 4-weeks or 8-weeks. At each time point, behavior was assessed using 3-chamber choice task and optomotor response; tissue was then collected and levels of inflammatory markers, tight junction proteins, and neurotransmitters determined using Western Blots. After 4-weeks, brain levels of v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RelA; NF-kB subunit), IkB kinase (IKK), and glial fibrillary acidic protein (GFAP) were significantly elevated; differences in zonula occludens-1 (ZO-1), claudin-5, glutamic acid decarboxylase (GAD), and tyrosine hydroxylase (TH) were not significant. In retina, significant differences were observed only for TH (decreased), Rel A (increased), and GFAP (increased) levels. Glucose-specific differences in initial choice latency and discrimination ratios were also observed. After 8-weeks, RelA, GAD, and TH were significantly elevated in both tissues; IKK and GFAP levels were also elevated, though not significantly. ZO-1 and claudin-5 levels osmotically decreased in retina but displayed an increasing trend in glucose-treated brains. Differences in discrimination ratio were driven by osmotic load. OMRs increased in glucose-treated fish at both ages. In vivo analysis of retinal vasculature suggested thicker vessels after 4-weeks, but thinner vessels at 8-weeks. In vitro, glucose treatment reduced formation of nodes and meshes in 3B-11 endothelial cells, suggesting a reduced ability to form a vascular network. Overall, hyperglycemia triggered a strong inflammatory response causing initial trending changes in tight junction and neuronal markers. Most differences after 4-weeks of exposure were observed in glucose-treated fish suggesting effects on glucose metabolism independent of osmotic load. After 8-weeks, the inflammatory response remained and glucose-specific effects on neurotransmitter markers were observed. Osmotic differences impacted cognitive behavior and retinal protein levels; protein levels in brain displayed glucose-driven changes. Thus, we not only observed differential sensitivities of retina and brain to glucose-insult, but also different cellular responses, suggesting hyperglycemia causes complex effects at the cellular level and/or that zebrafish are able to compensate for the continued high blood glucose levels.

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Upregulated inflammatory associated factors and blood-retinal barrier changes in the retina of type 2 diabetes mellitus model

Abstract: BRB permeability increases significantly in rats with type-2 DM, which may be associated with the up-regulated retinal expression of HMGB-1 and ICAM-1.

Cited by 6 publications

References 26 publications

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

miR-Let7A Controls the Cell Death and Tight Junction Density of Brain Endothelial Cells under High Glucose Condition

The Complex Relationship between Diabetic Retinopathy and High-Mobility Group Box: A Review of Molecular Pathways and Therapeutic Strategies

Time dependent effects of prolonged hyperglycemia in zebrafish brain and retina

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