Role of IL-6 in Angiotensin II–Induced Retinal Vascular Inflammation

Rojas, Modesto; Zhang, Wenbo; Lee, Dexter L.; Romero, Maritza J.; Nguyen, Doan T.; Al‐Shabrawey, Mohamed; Tsai, Nai Tse; Liou, Gregory I.; Brands, Michael; Caldwell, Robert W.; Caldwell, Ruth B.

doi:10.1167/iovs.09-3375

Cited by 77 publications

(66 citation statements)

References 35 publications

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“…This ischemia induces the activity of hypoxia-induced factor (HIF) which up-regulates VEGF expression and the transcription of various other angiogenic factors (Ozaki et al 1999). In addition to the ischemic stimulus, VEGF expression is also increased by inflammatory mediators (Rojas et al 2010). The role of VEGF in PDR is supported by studies that reported high concentrations of VEGF in the vitreous of patients with PDR and its excellent correlation with disease activity (Aiello et al 1994;Adamis et al 1999).…”

Section: Angiogenic Mechanisms In Proliferative Diabetic Retinopathymentioning

confidence: 94%

Antiangiogenic Therapy for Ischemic Retinopathies

Al-Latayfeh¹,

Silva²,

Sun³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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Section: Angiogenic Mechanisms In Proliferative Diabetic Retinopathymentioning

confidence: 94%

Antiangiogenic Therapy for Ischemic Retinopathies

Al-Latayfeh¹,

Silva²,

Sun³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

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“…Superoxide production was evaluated in retinal frozen sections collected at 6 h after I/R by the dihydroethidium (DHE) method, as described previously [28, 29]. Briefly, frozen sections were stained with DHE (2 μM) for 20 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective effect of water-dispersible hesperetin in retinal ischemia reperfusion injury

et al. 2015

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Purpose To determine whether water-dispersible hesperetin (WD-Hpt) can prevent degeneration of ganglion cell neurons in the ischemic retina. Methods Ischemia reperfusion (I/R) injury was induced by increasing the intraocular pressure of mice to 110 mmHg for 40 min. Mice received daily intraperitoneal injections with either normal saline (NS, 0.3 ml/day) or WD-Hpt (0.3 ml, 200 mg/kg/day). Reactive oxygen species (ROS) was assessed by dihydroethidium and nitrotyrosine formation. Inflammation was estimated by microglial morphology in the retina. Lipopolysaccharide (LPS)-stimulated BV-2 cells were used to explore the anti-inflammatory effect of WD-Hpt on activated microglia by quantifying the expression of IL-1β using real-time quantitative reverse transcription-polymerase chain reaction. Ganglion cell loss was assessed by immunohistochemistry of NeuN. Glial activation was quantified with glial fibrillary acidic protein (GFAP) immunoreactivity. Apoptosis was evaluated with a terminal deoxynucleotidyl transferase (TUNEL) assay and immunohistochemistry of cleaved caspase-3. Phosphorylation of extracellular signal-regulated kinase (p-ERK) was surveyed by western blotting. Results WD-Hpt decreased I/R-induced ROS formation. WD-Hpt alleviated microglial activation induced by I/R and reduced mRNA levels of IL-1β in LPS-stimulated BV-2. I/R resulted in a 37 % reduction in the number of ganglion cells in the NS-treated mice, whereas the reduction was only 5 % in the WD-Hpt-treated mice. In addition, WD-Hpt mitigated the immunoreactivity of GFAP, increased expression of cleaved caspase-3, increased number of TUNEL positive cells and p-ERK after I/R. Conclusions WD-Hpt protected ganglion cells from I/R injury by inhibiting oxidative stress and modulating cell death signaling. Moreover, WD-Hpt had an anti-inflammatory effect through the suppression of activated microglia.

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“…In addition, the diabetes-associated increase of leukostasis, which directly contributes to capillary nonperfusion in rodents, 26e28 is mediated largely by the increase of Ang II and the subsequent increase of NADPH oxidase and O 2 À . 31 For example, in nondiabetic animals, 31,32 intravitreal administration of Ang II increases leukostasis to comparable levels seen in diabetes. Ang II also sensitizes endothelial cells to tumor necrosis factor (TNF)-aeinduced ICAM-1 expression and monocyte adhesion, which implies that Ang II is an autocrine regulator of endothelial cell inflammatory responses.…”

Section: Retinal Overexpression Of Ace2 May Attenuate Vasodegeneratiomentioning

confidence: 99%

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

Dominguez

Caballero

et al. 2016

The American Journal of Pathology

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Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)eACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)echimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrowederived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP þ cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 AE 1.4; ACE2 diabetic, 6.4 AE 0.9 per mm 2 ) and partially reversed (reversal cohort: untreated diabetic, 15.7 AE 1.9; ACE2 diabetic, 6.5 AE 1.2 per mm 2 ) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80 þ ) (prevention cohort: untreated diabetic, 24.2 AE 6.7; ACE2 diabetic, 2.5 AE 1.6 per mm 2 ; reversal cohort: untreated diabetic, 56.8 AE 5.2; ACE2 diabetic, 5.6 AE 2.3 per mm 2 ). In both study cohorts, intracapillary bone marrowederived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system. (Am J Pathol 2016, 186: 1688e1700; http://dx

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Role of IL-6 in Angiotensin II–Induced Retinal Vascular Inflammation

Abstract: The results indicate that IL-6 expression is essential for angiotensin II-induced increases in retinal VEGF expression, leukostasis, and vascular remodeling. The data suggest a critical role for IL-6 in mediating angiotensin II-induced retinal vascular inflammation and remodeling.

Cited by 77 publications

References 35 publications

Antiangiogenic Therapy for Ischemic Retinopathies

Antiangiogenic Therapy for Ischemic Retinopathies

Neuroprotective effect of water-dispersible hesperetin in retinal ischemia reperfusion injury

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

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