Role of nitric oxide, superoxide, peroxynitrite and PARP in diabetic retinopathy

Zheng, Ling; Kern, Timothy S.

doi:10.2741/3505

Cited by 106 publications

(91 citation statements)

References 150 publications

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“…Diabetes results in mitochondrial defects in multiple tissues including the retina, and prominent among these abnormalities is the increased generation of superoxide (1,4,5,11,17,(38)(39)(40). We previously reported that mitochondria are major contributors to diabetes-induced generation of superoxide by retina (11).…”

Section: Discussionmentioning

confidence: 99%

“…T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1,2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3)(4)(5)(6)(7).…”

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confidence: 99%

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Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

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

281

285

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Accumulating evidence suggests that photoreceptor cells play a previously unappreciated role in the development of early stages of diabetic retinopathy, but the mechanism by which this occurs is not clear. Inhibition of oxidative stress is known to inhibit the vascular lesions of early diabetic retinopathy, and we investigated whether the diabetes-induced oxidative stress in the retina emanates from photoreceptors. Superoxide generation was assessed in retinas of male C57BL/6J mice made diabetic for 2 mo (4 mo of age when killed) using histochemical (dichlorofluorescein and dihydroethidine) and bioluminescence (lucigenin) methods. Photoreceptors were eliminated in vivo by genetic (opsin −/− ) and chemical (iodoacetic acid) techniques. Immunoblots were used to measure expression of intercellular adhesion molecule 1 and the inducible form of nitric oxide synthase. Diabetes increased the generation of superoxide by diabetic mouse retina more at night than during the day. Photoreceptors were the major source of reactive oxygen species in the retina, and their deletion (either genetically in opsin −/− mice or acutely with iodoacetic acid) inhibited the expected diabetes-induced increase in superoxide and inflammatory proteins in the remaining retina. Both mitochondria and NADPH oxidase contributed to the observed retinal superoxide generation, which could be inhibited in vivo with either methylene blue or apocynin. Photoreceptors are the major source of superoxide generated by retinas of diabetic mice. Pharmaceuticals targeting photoreceptor oxidative stress could offer a unique therapy for diabetic retinopathy.T he pathogenesis of diabetic retinopathy remains unclear, but prior work by us and others has provided strong evidence in animal models that oxidative stress and inflammatory processes play important roles in the development of the vascular lesions characteristic of early stages of this retinopathy (1, 2). Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3-7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8-10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2). However, which cells of the retina are the major sources of such oxidative stress in diabetes is unclear. In vitro studies of retinal endothelial cells or Müller cells incubated in elevated levels of glucose have demonstrated that these cells can contribute to oxidative stress (11, 12), but the contribution of other cell types and their relative importance has not been studied.Rod and cone photoreceptor cells are the most prevalent cells in the retina. These postmitotic cells have a very high metabolic rate, using more oxygen than other cells throughout the body. They are also considered as likely contributors to the eventual development of retinal hypoxia and subsequent neovascularization in advanced stages of diabetic retinopathy (13,14). Th...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Veenstra

Palczewski

et al. 2013

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

281

285

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“…Biological nitrosylation of protein tyrosine is a phenomenon that is associated with a wide range of pathological conditions, including ocular inflammation [21] , and protein nitrosylation is a post-translational modification biomarker of oxidative stress [22] . At present, the role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic micro-and macrovascular com- plications is under active investigation [23,24] , and the evidence for protein nitrosylation in vivo is solid [9] , although there is some discussion as to the main nitrating mechanism involved [25] . Increased nitrosative stress has been suggested in diabetic retinopathy in animal models [26,27] , but to our knowledge few data are available in humans.…”

Section: Discussionmentioning

confidence: 99%

Diabetic Retinopathy Is Associated with Decreased Tyrosine Nitrosylation of Vitreous Interleukins IL-1α, IL-1β, and IL-7

Reverter

Nadal²,

Ballester³

et al. 2011

Ophthalmic Res

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Objective: To simultaneously evaluate tyrosine nitrosylation and phosphorylation levels of vitreous interleukins of patients with diabetic retinopathy, in which abnormal tyrosine phosphorylation has been previously described. Research Design and Methods: Specific immunoprecipitation of interleukins IL-1α, IL-1β, IL-2 and IL-7 was carried out in samples obtained during vitrectomy performed for proliferative diabetic retinopathy in patients (n = 12) and for macular hole in controls (n = 12). Tyrosine nitrosylation and phosphorylation levels of the immunoprecipitated interleukins were analysed by Western blot with the respective specific antibodies and correlated. The results were also correlated with the total amount of immunoprecipitated interleukin protein. The mean phosphorylation/nitrosylation ratios of these proteins in vitreous humour of both the control group and diabetic patients were determined. Results: Diabetes was associated with decreased tyrosine nitrosylation of IL-1α, IL-1β and IL-7 and an increased tyrosine phosphorylation/nitrosylation ratio with respect to controls in IL-1α (1.58 ± 0.22 vs. 2.74 ± 0.39, respectively; p < 0.05) and IL-7 (2.15 ± 0.01 vs. 3.26 ± 0.57, respectively; p < 0.05). No significant changes were observed in nitrotyrosine or in the tyrosine phosphorylation/nitrosylation ratio of IL-2. Conclusions:Proliferative diabetic retinopathy is associated with concomitant and simultaneous changes in both tyrosine phosphorylation and tyrosine nitrosylation status of specific pro-inflammatory interleukins present in the vitreous fluid such as IL-1α, IL-1β and IL-7. These changes could be related to the increase in pro-inflammatory activity detected in diabetes-induced retinopathy.

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“…N ε -(Carboxymethyl) lysine (CML) is one well characterised glycoxidation product, which serves as a biomarker of general oxidative stress, accumulates in tissues with age and whose rate of accumulation is accelerated in diabetes [6][7][8]. ROS, in particular superoxide anions, interact with nitric oxide, forming the strong cytotoxin, peroxynitrite, which attacks various biomolecules, leading to the production of a modified amino acid nitrotyrosine [9]. Nitrotyrosine measurements have been established as a biomarker of nitrosative stress, which is implicated as a key mechanism in diabetic pathologies, affecting enzyme activities, antioxidant capacities, signal transduction and DNA integrity [10].…”

Section: Introductionmentioning

confidence: 99%

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

et al. 2010

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Aims/hypothesis Diabetic retinopathy is the result of increased oxidative and nitrosative stress induced by chronic hyperglycaemia, and affects the vasculature and the neuroglia. Erythropoietin is a neuroprotective and an endothelial survival factor. We assessed the effect of suberythropoietic epoetin delta doses on variables of oxidative stress in target tissues of diabetic complications and on pericyte loss in the diabetic retina. Methods We administered epoetin delta to streptozotocininduced diabetic Wistar rats at doses of 384 IU/kg body weight once weekly or 128 IU/kg body weight three times a week. The treatment lasted for 3 months. Oxidative stress and formation of AGEs were assessed by immunoblotting, expression of Ang-2 (also known as Angpt2) by RT-PCR, activation of protein kinase B (AKT) and heat shock protein (HSP)-27 levels by immunofluorescence, and incipient retinal vascular changes by quantitative morphometry of retinal digest preparations. Results Diabetes increased variables of oxidative stress and nitrosative stress (N ε -carboxymethyl-lysine, nitrotyrosine and methylglyoxal-type AGEs) in retina, kidney and heart of diabetic rats. Epoetin delta reduced oxidative and nitrosative stress in all tissues, and AGEs in the retina. It also reduced increased retinal Ang-2 expression and pericyte loss, and ameliorated p-AKT and HSP-27 levels. Conclusions/interpretation Epoetin delta has antioxidative properties in organs affected by diabetes and may prevent incipient microvascular damage in the diabetic retina.

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Role of nitric oxide, superoxide, peroxynitrite and PARP in diabetic retinopathy

Cited by 106 publications

References 150 publications

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Photoreceptor cells are major contributors to diabetes-induced oxidative stress and local inflammation in the retina

Diabetic Retinopathy Is Associated with Decreased Tyrosine Nitrosylation of Vitreous Interleukins IL-1α, IL-1β, and IL-7

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina

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