Intravitreal administration of endothelin type A receptor or endothelin type B receptor antagonists attenuates hypertensive and diabetic retinopathy in rats

Alrashdi, Saeed F.; Deliyanti, Devy; Wilkinson-Berka, Jennifer L.

doi:10.1016/j.exer.2018.06.025

Cited by 11 publications

(10 citation statements)

References 52 publications

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“…36,37 Our findings are consistent with our previous studies in diabetic rats demonstrating that retinal Müller cell gliosis and VEGF levels are increased as well as vascular leakage into the retina and vitreous, and that these events are exacerbated by systemic hypertension. 38 We also identified that angiopoietin-2 levels are increased in retinas of diabetic WKY and SHR, which is of interest due to the ability of this factor to potentiate the actions of VEGF. 39 Another indication that the integrity of the BRB was compromised in diabetic WKY and SHR was the reduced expression levels of ZO-1 and occludin which were further lowered by the combination of hypertension and diabetes.…”

Section: Discussionmentioning

confidence: 83%

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

et al. 2020

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Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin + Nox5 + mice). In vascular endothelial-cadherin + Nox5 + mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose–induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature.

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Section: Discussionmentioning

confidence: 83%

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

et al. 2020

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“…There are indications that ET activity may be involved in DR, and evidence has been provided that ET inhibition may ameliorate the pathologic signs of DR. Indeed, an ETRA antagonist has been reported to block the diabetes-induced upregulation of both VEGF and ICAM-1 in retinas of STZ rats (Masuzawa et al, 2006), while other observations have described positive effects of ETR inhibition on both neuronal and vascular changes seen in DR. For instance, ETRA and/or ETRB inhibitors reduced retinal thinning, the number of apoptotic cells, and the levels of the pro-inflammatory cytokine TNFα in diabetic rat retinas, and at the same time they also reduced pericyte loss, capillary degeneration, vascular leakage, and the levels of both VEGF and ICAM-1 (Chou et al, 2014; Alrashdi et al, 2018; Bogdanov et al, 2018).…”

Section: Neuropeptidesmentioning

confidence: 99%

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

2019

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Diabetic retinopathy (DR) is a common complication of diabetes and constitutes a major cause of vision impairment and blindness in the world. DR has long been described exclusively as a microvascular disease of the eye. However, in recent years, a growing interest has been focused on the contribution of neuroretinal degeneration to the pathogenesis of the disease, and there are observations suggesting that neuronal death in the early phases of DR may favor the development of microvascular abnormalities, followed by the full manifestation of the disease. However, the mediators that are involved in the crosslink between neurodegeneration and vascular changes have not yet been identified. According to our hypothesis, vascular endothelial growth factor (VEGF) could probably be the most important connecting link between the death of retinal neurons and the occurrence of microvascular lesions. Indeed, VEGF is known to play important neuroprotective actions; therefore, in the early phases of DR, it may be released in response to neuronal suffering, and it would act as a double-edged weapon inducing both neuroprotective and vasoactive effects. If this hypothesis is correct, then any retinal stress causing neuronal damage should be accompanied by VEGF upregulation and by vascular changes. Similarly, any compound with neuroprotective properties should also induce VEGF downregulation and amelioration of the vascular lesions. In this review, we searched for a correlation between neurodegeneration and vasculopathy in animal models of retinal diseases, examining the effects of different neuroprotective substances, ranging from nutraceuticals to antioxidants to neuropeptides and others and showing that reducing neuronal suffering also prevents overexpression of VEGF and vascular complications. Taken together, the reviewed evidence highlights the crucial role played by mediators such as VEGF in the relationship between retinal neuronal damage and vascular alterations and suggests that the use of neuroprotective substances could be an efficient strategy to prevent the onset or to retard the development of DR.

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“…Taken together, these results indicate that BQ123 can activate PMN-MDSCs but not M-MDSCs in mice, and that Arg1 is involved in BQ123-induced PMN-MDSC-mediated immunosuppression. Previous studies have reported that the effect of BQ123 on various diseases depends on the ET1-ETAR system (10)(11)(12)14). To better understand the nature of the BQ123-derived PMN-MDSC, we performed additional experiments.…”

Section: Bq123 Promoted Pmn-mdsc Activation In Micementioning

confidence: 99%

“…The ET1/ETAR system blocking with BQ123 may have clinical applications in the treatment of septic shock (9). It has also been reported that BQ123 can reduce the expression of proinflammatory cytokines, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-a, interleukin (IL)-1, and IL-6, by regulating the ET1/ ETAR system (10)(11)(12). BQ123 may also play a role in alleviating chronic airway inflammatory obstructive asthma by reducing fibrocyte differentiation and progression (13).…”

Section: Introductionmentioning

confidence: 99%

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

Chen

Zhang

et al. 2021

Front. Immunol.

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The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.

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Intravitreal administration of endothelin type A receptor or endothelin type B receptor antagonists attenuates hypertensive and diabetic retinopathy in rats

Cited by 11 publications

References 52 publications

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy

Relationships Between Neurodegeneration and Vascular Damage in Diabetic Retinopathy

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

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