Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

Obrosova, Irina G.; Drel, Viktor R.; Kumagai, Arno K.; Szabó, Csaba; Pacher, Pál; Stevens, Martin J.

doi:10.1007/s00125-006-0356-7

Cited by 82 publications

(66 citation statements)

References 44 publications

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“…Perhaps there is a functional relationship between ANG II, superoxide, and retina neuronal function. Increased oxidative stress has been observed in the diabetic retina (45). Although we have documented that ANG II increases superoxide formation in the retina, at least in part by activating NAD(P)H oxidase activity, it is possible that in diabetes a deficiency in the retina antioxidant defense activity may be an important contributor to the enhanced oxidative stress.…”

Section: Discussionmentioning

confidence: 79%

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

Chen¹,

Guo²,

Edwards³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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We studied whether angiotensin II (ANG II) via superoxide may contribute to retinal leukostasis and thus to the pathogenesis of retinopathies. We studied: 1) whether intravitreal ANG II induces retinal leukostasis that is altered by antioxidants or by apocynin, a NAD(P)H oxidase inhibitor and 2) whether retinal leukostasis induced by diabetes in rats is also altered by these treatments. Rats were injected intravitreally with ANG II (20 g in 2 l), and divided into the following three groups: 1) untreated; 2) treated with tempol doses (ϳ3 mM/day) and N-acetylcysteine (NAC; ϳ1 g⅐ kg Ϫ1 ⅐ day Ϫ1 ); and 3) treated with apocynin (ϳ2 mM/day), both in the drinking water. Rats with streptozotocin-induced diabetes were similarly treated. Leukostasis was evaluated 48 h after ANG II or 2 wk after diabetes induction. ANG II increased retinal leukostasis from 0.3 Ϯ 0.5 to 3.7 Ϯ 0.4 leukocytes/ mm 2 (P Ͻ 0.01), and these changes were markedly decreased by treatment with tempol ϩ NAC or apocynin, and also by a blocking antibody against vascular endothelial growth factor given intravitreally (P Ͻ 0.01). In addition, incubation of dihydroethidium-loaded retina sections with ANG II caused marked increase in superoxide formation. Compared with normal controls, retinal leukostasis in diabetic rats markedly increased from 0.2 Ϯ 0.3 to 3.8 Ϯ 0.1 leukocytes/mm 2 (P Ͻ 0.01). Diabetic retinal leukostasis was also decreased by treatment with tempol-NAC and normalized by apocynin. Thus increases in intravitreal ANG II can induce retinal leukostasis, which appears to be mediated via increasing superoxide generation by NAD(P)H oxidase, and by VEGF. The activity of NAD(P)H oxidase is required for leukostasis to occur in the diabetic retina.renin-angiotensin system; angiotensin ii; angiotensin receptor antagonists; diabetes; retinal leukostasis; NAD(P)H oxidase superoxide; vascular endothelial growth factor DIABETIC RETINOPATHY is a major cause of blindness (2, 3) that is characterized by progressive alterations in the retinal microvasculature, manifested by areas of nonperfusion, increased permeability, leaky microaneurysms, and pathological angiogenesis. Two sets of observations suggest that the reninangiotensin system (RAS) may contribute to the pathogenesis of diabetic retinopathy. First, the components of the RAS are present in the eye, and intraocular and serum levels of ANG II, renin, and angiotensin-converting enzyme (ACE) reportedly correlate significantly with the severity of retinopathy (10, 16 -18, 52, 56). Second, ACE inhibitors (ACEi) reportedly arrest or delay progressive breakdown of the blood-retina barrier in normotensive insulin-dependent diabetic patients with nephropathy and have favorable effects on normotensive patients with insulin-dependent diabetic retinopathy (21). These finding suggest the possibility that ANG II acts as an endocrine/paracrine factor and thereby influences the development of diabetic retinopathy, as proposed by some investigators (59).Recent evidence suggests that leukocytes may be involved in the ...

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Section: Discussionmentioning

confidence: 79%

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

Chen¹,

Guo²,

Edwards³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The goal of this study was to determine the temporal relationship between RDN and microvascular manifestations of DM, including DR. We did not focus on identifying the pathophysiological mechanisms, because compelling mechanistic data from previous studies demonstrate neural apoptosis, glial cell reactivity, and numerous aberrant biochemical pathways associated with RDN that appear to be independent of vascular changes (3,32,43,44). In the retina, glial, neural, and vascular cells are closely associated in a socalled "neurovascular unit" to maintain the homeostasis necessary for normal neuroretinal function (1).…”

Section: Discussionmentioning

confidence: 99%

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Sohn

Dijk

Jiao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

493

437

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Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr db /J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications.diabetes | retina | neurodegeneration | diabetic retinopathy | optical coherence tomography

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“…Hyperglycemia may lead to both impaired antioxidant protection (40) and increased production of ROS by vascular endothelium (9,27,41). The effect of the altered redox balance in endothelial cells is likely to contribute to the onset of endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species downregulate glucose transport system in retinal endothelial cells

Fernandes

Hosoya

Pereira³

2011

American Journal of Physiology-Cell Physiology

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Fernandes R, Hosoya K, Pereira P. Reactive oxygen species downregulate glucose transport system in retinal endothelial cells. Am J Physiol Cell Physiol 300: C927-C936, 2011. First published January 12, 2011; doi:10.1152/ajpcell.00140.2010.-Retinal endothelial cells are believed to play an important role in the pathogenesis of diabetic retinopathy. In previous studies, we and others demonstrated that glucose transporter 1 (GLUT1) is downregulated in response to hyperglycemia. Increased oxidative stress is likely to be the event whereby hyperglycemia is transduced into endothelial cell damage. However, the effects of sustained oxidative stress on GLUT1 regulation are not clearly established. The objective of this study is to evaluate the effect of increased oxidative stress on glucose transport and on GLUT1 subcellular distribution in a retinal endothelial cell line and to elucidate the signaling pathways associated with such regulation. Conditionally immortalized rat retinal endothelial cells (TRiBRB) were incubated with glucose oxidase, which increases the intracellular hydrogen peroxide levels, and GLUT1 regulation was investigated. The data showed that oxidative stress did not alter the total levels of GLUT1 protein, although the levels of mRNA were decreased, and there was a subcellular redistribution of GLUT1, decreasing its content at the plasma membrane. Consistently, the half-life of the protein at the plasma membrane markedly decreased under oxidative stress. The proteasome appears to be involved in GLUT1 regulation in response to oxidative stress, as revealed by an increase in stabilization of the protein present at the plasma membrane and normalization of glucose transport following proteasome inhibition. Indeed, levels of ubiquitinated GLUT1 increase as revealed by immunoprecipitation assays. Furthermore, data indicate that protein kinase B activation is involved in the stabilization of GLUT1 at the plasma membrane. Thus subcellular redistribution of GLUT1 under conditions of oxidative stress is likely to contribute to the disruption of glucose homeostasis in diabetes.glucose transporter 1; oxidative stress; protein kinase B; proteasome; retinal endothelial cells; reactive oxygen species REACTIVE OXYGEN SPECIES (ROS) such as hydrogen peroxide (H 2 O 2 ) and superoxide anion are constantly produced intracellularly as a result of normal metabolic activity.

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Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models

Cited by 82 publications

References 44 publications

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis

Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus

Reactive oxygen species downregulate glucose transport system in retinal endothelial cells

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