VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases

Le, Yun-Zheng

doi:10.1016/j.visres.2017.05.005

Cited by 93 publications

(71 citation statements)

References 67 publications

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“…Despite the efficacy of these molecules in the improvement of visual acuity, repeated intravitreal injections of anti‐VEGF may cause long‐term ocular complications given the important role of VEGF in maintaining vascular integrity and survival of neuronal cells (Fontaine et al, ; Park, Kim, & Park, ; Saint‐Geniez et al, ; Wilkinson‐Berka & Miller, ). VEGF appears to be neuroprotective, and a loss of this factor could result in retinal ganglion cell loss potentiated by decreased retinal blood flow (Le, ). The anti‐VEGF treatment can potentially increase the risk of endophthalmitis (Reibaldi et al, ) and development of geographical atrophy (Gemenetzi, Lotery, & Patel, ).…”

Section: Introductionmentioning

confidence: 99%

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Hachana

Fontaine

Sapieha

et al. 2020

British J Pharmacology

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Background and Purpose: Age-related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti-VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro-inflammatory kallikreinkinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti-VEGF and anti-B 1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV). Experimental Approach: Immediately after laser-induced CNV, Long-Evans rats were treated by eye-drop application of a B 1 receptor antagonist (R-954) or by intravitreal injection of B 1 receptor siRNA or anti-VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood-retinal barrier was measured 10 days later in the retina. B 1 receptor and VEGF-R2 cellular localization was assessed. Key Results: The three treatments significantly inhibited the CNV-induced retinal changes. Anti-VEGF and R-954 decreased CNV-induced up-regulation of B 1 and B 2 receptors, TNF-α, and ICAM-1. Anti-VEGF additionally reversed up-regulation of VEGF-A, VEGF-R2, HIF-1α, CCL2 and VCAM-1, whereas R-954 inhibited gene expression of IL-1β and COX-2. Enhanced retinal vascular permeability was abolished by anti-VEGF and reduced by R-954 and B 1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti-VEGF and B 1 receptor inhibition. B 1 receptors were found on astrocytes and endothelial cells.Conclusion and Implications: B 1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser-induced CNV. The non-invasive, selfadministration of B 1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.

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Section: Introductionmentioning

confidence: 99%

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Hachana

Fontaine

Sapieha

et al. 2020

British J Pharmacology

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“…Among numerous cytokines and growth factors involved in the pathogenesis of DR, vascular endothelial growth factor (VEGF)‐A is a key mediator for ischaemia‐induced retinal neovascularization and inflammation . Dysfunction of Müller glial cells affected in the ischaemic retina promotes the angiogenic activity of DR as the major source of VEGF‐A overproduction …”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Kanda

Hirose

Noda

et al. 2020

J Cellular Molecular Medi

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Galectin-1/LGALS1, a newly recognized angiogenic factor, contributes to the pathogenesis of diabetic retinopathy (DR). Recently, we demonstrated that glucocorticoids suppressed an interleukin-1β-driven inflammatory pathway for galectin-1 expression in vitro and in vivo. Here, we show glucocorticoid-mediated inhibitory mechanism against hypoxia-inducible factor (HIF)-1α-involved galectin-1 expression in human Müller glial cells and the retina of diabetic mice. Hypoxia-induced increases in galectin-1/LGALS1 expression and promoter activity were attenuated by dexamethasone and triamcinolone acetonide in vitro. Glucocorticoid application to hypoxia-stimulated cells decreased HIF-1α protein, but not mRNA, together with its DNA-binding activity, while transactivating TSC22 domain family member (TSC22D)3 mRNA and protein expression. Co-immunoprecipitation revealed that glucocorticoid-transactivated TSC22D3 interacted with HIF-1α, leading to degradation of hypoxia-stabilized HIF-1α via the ubiquitin-proteasome pathway. Silencing TSC22D3 reversed glucocorticoid-mediated ubiquitination of HIF-1α and subsequent down-regulation of HIF-1α and galectin-1/LGALS1 levels. Glucocorticoid treatment to mice significantly alleviated diabetes-induced retinal HIF-1α and galectin-1/Lgals1 levels, while increasing TSC22D3 expression. Fibrovascular tissues from patients with proliferative DR demonstrated co-localization of galectin-1 and HIF-1α in glial cells partially positive for TSC22D3. These results indicate that glucocorticoid-transactivated TSC22D3 attenuates hypoxia-and diabetes-induced retinal glial galectin-1/LGALS1 expression via HIF-1α destabilization, highlighting therapeutic implications for DR in the era of anti-vascular endothelial growth factor treatment. K E Y W O R D S diabetic retinopathy, galectin-1, glucocorticoid, HIF-1α, hypoxia, Müller glia, transactivation, TSC22D3

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“…Anti-VEGF therapies have been developed, and are effective for reduction of diabetic macular oedema and improvement of visual outcomes in individuals with diabetes [8]. In addition to VEGF, a number of other proinflammatory cytokines, such as TNF-α and intercellular adhesion molecule 1 (ICAM-1), are upregulated at the early stage of diabetic retinopathy [9], and high levels of proinflammatory cytokines are observed in the vitreous of individuals with proliferative diabetic retinopathy [10] and in the retinas of animal models of diabetes [11]. Ablation of TNF-α suppresses leucostasis and reduces vascular permeability in diabetic retinopathy [12], suggesting that dysregulation of cytokine production contributes to pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Loss of X-box binding protein 1 in Müller cells augments retinal inflammation in a mouse model of diabetes

et al. 2019

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Aims/hypothesis Müller glia (MG) are major sources of retinal cytokines, and their activation is closely linked to retinal inflammation and vascular leakage in diabetic retinopathy. Previously, we demonstrated that X-box binding protein 1 (XBP1), a transcription factor activated by endoplasmic reticulum (ER) stress in diabetic retinopathy, is involved in regulation of inflammation in retinal endothelial cells. Now, we have explored the role of XBP1 and ER stress in the regulation of MGderived proinflammatory factors, and their influence on vascular permeability in diabetic retinopathy. Methods MG-specific conditional Xbp1 knockout (Xbp1 Müller−/− ) mice were generated by crossing Xbp1 flox/flox mice with Müller-Cre transgenic mice. Diabetes was modelled by induction with streptozotocin, and retinal vascular permeability was measured with FITC-conjugated dextran 2 months after induction. Primary Müller cells were isolated from Xbp1 Müller−/− and Xbp1 Müller+/+ mice and exposed to hypoxia and high levels of glucose. Levels of ER-stress and inflammatory factors were examined by real-time PCR, western blotting or immunohistochemistry. Results Xbp1 Müller−/− mice exhibited normal retinal development and retinal function and expressed similar levels of ER-stress and inflammatory genes to Xbp1 Müller+/+ littermates. In diabetes-inducing conditions, compared with Xbp1 Müller+/+ mice, Xbp1 Müller−/− mice had higher mRNA levels of retinal Vegf (also known as Vegfa) and Tnf-α (also known as Tnf) and ERstress marker genes Grp78 (also known as Hspa5), Atf4, Chop (also known as Ddit3) and Atf6 and higher protein levels of vascular endothelial growth factor (VEGF), TNF-α, phospho-c-Jun N-terminal kinase (JNK), 78 kDa glucose-regulated protein (GRP78), phospho-eukaryotic translation initiation factor (eIF)2α and activating transcription factor (ATF)6. Retinal vascular permeability was significantly higher in diabetic Xbp1 Müller−/− mice than in diabetic Xbp1 Müller+/+ mice (p < 0.01). Results obtained in vitro with primary Müller cells isolated from Xbp1 Müller−/− mice confirmed higher expression levels of inflammatory and ER-stress markers (but not GRP78) than in cells from Xbp1 Müller+/+ mice. Moreover, XBP1-deficient Müller cells were more susceptible to high-glucose-or hypoxia-induced ER stress and inflammation than cells from Xbp1 Müller+/+ mice. Inhibition of ER stress with chemical chaperones suppressed hypoxia-induced VEGF and TNF-α production in XBP1-deficient Müller cells.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-018-4776-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases

Cited by 93 publications

References 67 publications

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Loss of X-box binding protein 1 in Müller cells augments retinal inflammation in a mouse model of diabetes

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VEGF production and signaling in Müller glia are critical to modulating vascular function and neuronal integrity in diabetic retinopathy and hypoxic retinal vascular diseases

Cited by 93 publications

References 67 publications

The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

Glucocorticoid‐transactivated TSC22D3 attenuates hypoxia‐ and diabetes‐induced Müller glial galectin‐1 expression via HIF‐1α destabilization

Loss of X-box binding protein 1 in Müller cells augments retinal inflammation in a mouse model of diabetes

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The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization

The effects of anti‐VEGF and kinin B₁ receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization