Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Zheng, Ling; Du, Yunpeng; Miller, Clinton; Gubitosi-Klug, Rose; Kern, Timothy S.; Ball, Sherry L.; Berkowitz, Bruce A.

doi:10.1007/s00125-007-0734-9

Cited by 196 publications

(157 citation statements)

References 49 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%

“…Several proinflammatory proteins, including the inducible form of nitric oxide synthase (iNOS) and intercellular adhesion molecule 1 (ICAM-1), are induced in the retina in diabetes and have been shown to play a critical role in the pathogenesis of the vascular degeneration that occurs in diabetic retinopathy (5,21). Thus, we investigated if the increased expression of iNOS and ICAM-1 are related to changes occurring in photoreceptors in diabetes.…”

Section: Consequences Of Diabetes-induced Oxidative Stress In Photorementioning

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).…”

mentioning

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.

271

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%

Section: Consequences Of Diabetes-induced Oxidative Stress In Photorementioning

confidence: 99%

mentioning

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.

271

285

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“…In the retina, iNOS is sensitive to hyperglycemia and responsible for overproduction of NO (30,31). The resulting surplus of NO is either quenched by advanced glycation end products (AGEs) or leads, through the reaction with superoxide, to the formation of peroxynitrite with subsequent nitrosylation of proteins, lipids, and DNA.…”

Section: Retinopathymentioning

confidence: 99%

Gasotransmitters in Vascular Complications of Diabetes

et al. 2016

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In the past decades three gaseous signaling molecules—so-called gasotransmitters—have been identified: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). These gasotransmitters are endogenously produced by different enzymes in various cell types and play an important role in physiology and disease. Despite their specific functions, all gasotransmitters share the capacity to reduce oxidative stress, induce angiogenesis, and promote vasorelaxation. In patients with diabetes, a lower bioavailability of the different gasotransmitters is observed when compared with healthy individuals. As yet, it is unknown whether this reduction precedes or results from diabetes. The increased risk for vascular disease in patients with diabetes, in combination with the extensive clinical, financial, and societal burden, calls for action to either prevent or improve the treatment of vascular complications. In this Perspective, we present a concise overview of the current data on the bioavailability of gasotransmitters in diabetes and their potential role in the development and progression of diabetes-associated microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (cerebrovascular, coronary artery, and peripheral arterial diseases) complications. Gasotransmitters appear to have both inhibitory and stimulatory effects in the course of vascular disease development. This Perspective concludes with a discussion on gasotransmitter-based interventions as a therapeutic option.

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“…54 Three different isoforms of NOS exist; two of which are constitutively expressed and are Ca 2+ dependent (endothelial, eNOS and neuronal, nNOS) and one which is induced by immunological signals due to sustained tissue damage (inducible, iNOS) 2 that is present in diseased states such as diabetic retinopathy. 55 Immunohistochemical staining evidence has suggested asymmetric localization of different NOS isoforms across the retina. 54 Although not examined in detail, Yamamoto et al have reported that the optic nerve axons are essentially absent of NOS activity in control rats.…”

Section: Nitrate Analysis In Rat Vitreous Perfusatesmentioning

confidence: 99%

Measurement of Region-Specific Nitrate Levels of the Posterior Chamber of the Rat Eye Using Low-Flow Push−Pull Perfusion

2008

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The determination of the presence of nitric oxide (NO) metabolites in the rat vitreous cavity in a regioselective manner is complicated by the size and shape of the eye as well as the diffusivity of the molecule and its metabolites. In this work, in vivo low-flow push-pull perfusion sampling was utilized with a rapid capillary electrophoretic assay to monitor levels of the major NO metabolite, nitrate, at the vitreoretinal interface (VRI) of normal and aged rat models. The sampling probe tips were placed in three different positions in the posterior chamber through a 29-gauge guide needle. Sampling was performed along the VRI over the optic nerve head and regions peripheral to the optic nerve head. Additionally, samples were collected from the middle vitreous region to compare to VRI sampling. A significant (P<0.05) difference in the perfusate nitrate concentration was observed in each location, which may be due to the source of NO production or the clearance mechanism of the molecule from vitreous cavity. Infusion of L-NAME with physiological saline led to a significant decrease (35%) in the observed nitrate level. LFPPP was then utilized to observe nitrate levels after an average of 4.5 months of aging. A 3-fold increase in the mean level of nitrate over the optic nerve head was observed in mature animals compared to younger control animals. Precise measurement of NO metabolites along the VRI may provide insights into the function of NO in maintaining homeostatic conditions and the molecular changes at the diseased retina.

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Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetes

Cited by 196 publications

References 49 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

Gasotransmitters in Vascular Complications of Diabetes

Measurement of Region-Specific Nitrate Levels of the Posterior Chamber of the Rat Eye Using Low-Flow Push−Pull Perfusion

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