Oxidative Damage in the Retinal Mitochondria of Diabetic Mice: Possible Protection by Superoxide Dismutase

Kanwar, Mamta; Chan, Pooi-See; Kern, Timothy S.; Kowluru, Renu A.

doi:10.1167/iovs.06-1280

Cited by 288 publications

(301 citation statements)

References 34 publications

(59 reference statements)

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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%

“…Inhibition of oxidative stress by feeding antioxidants or overexpressing antioxidant enzymes has reduced diabetes-induced degeneration of retinal capillaries (3)(4)(5)(6)(7). Moreover, oxidative stress has been reported to regulate expression of proinflammatory proteins (8)(9)(10), which also have been shown to play a critical role in the pathogenesis of this early retinopathy (2).…”

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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.

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280

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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.

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280

285

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“…It appears to be causally involved in the development of the retinopathy as oral administration of antioxidants 17 or genetic overexpression of superoxide dismutases 18 has been shown to inhibit the diabetes-induced degeneration of retinal capillaries in animal studies. Moreover, up-regulation of ROS can lead to increased activation of NF-kB, which, in turn, increased the release of proinflammatory cytokines and nitric oxide (NO).…”

Section: Oxidative Stressmentioning

confidence: 99%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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“…Mitochondrial superoxide are considered as the unifying molecules connecting many metabolic abnormalities associated with diabetic retinopathy [7,67,68], and in diabetes, retinal mitochondria are damaged and superoxide scavenging enzyme (superoxide dismutase) is dysfunctional [69]. We have shown that diabetes epigenetically modifies Sod2, the gene encoding mitochondrial superoxide dismutase, and H4K20me3, acetyl H3K9 and p65 subunit of NF-B (p65) are increased at its promoter/enhancer, H3K4 is demethylated and LSD1 binding is increased.…”

Section: Epigenetic Modification and Diabetesmentioning

confidence: 99%

Contribution of epigenetics in diabetic retinopathy

Kowluru

Mishra

2015

Sci. China Life Sci.

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Diabetes has become the epidemic of the 21st century, and with over 90% patients with diabetes becoming at a risk of developing retinopathy, diabetic retinopathy has emerged as a major public health concern. In spite of cutting edge research in the field, how retina and its vasculature are damaged by the diabetic milieu remains ambiguous. The environmental factors, life style or disease process can also bring in modifications in the DNA, and these epigenetic modifications either silence or activate a gene without altering the DNA sequence. Diabetic environment up-or downregulates a number of genes in the retina, and emerging research has shown that it also facilitates epigenetic modifications. In the pathogenesis of diabetic retinopathy, the genes associated with important enzymes (e.g., mitochondrial superoxide dismutase, matrix metalloproteinase-9 and thioredoxin interacting protein) and transcriptional factors are epigenetically modified, the enzymes responsible for these epigenetic modifications are either activated or inhibited, and the levels of microRNAs are altered. With epigenetic modifications taking an important place in diabetic retinopathy, it is now becoming critical to evaluate these modifications, and understand their impact on this slow progressing blinding disease. diabetic retinopathy, epigenetic modifications, histone acetylation, histone methylation, miRNA Citation:Kowluru RA, Mishra M. Contribution of epigenetics in diabetic retinopathy.

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Oxidative Damage in the Retinal Mitochondria of Diabetic Mice: Possible Protection by Superoxide Dismutase

Cited by 288 publications

References 34 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

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Contribution of epigenetics in diabetic retinopathy

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