Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus

El‐Asrar, Ahmed M. Abu; Desmet, Stefaan; Meersschaert, A; Dralands, L; Missotten, Luc; Geboes, Karel

doi:10.1016/s0002-9394(01)01127-8

Cited by 107 publications

(70 citation statements)

References 34 publications

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“…14,19,22,30,31,40 In particular, microglial cell activation was found to be an early marker of diabetic changes in different animal models and to potentially release neurotoxic agents at advanced stages of diabetes. Indeed activated microglia produce cytotoxic substances, such as tumor necrosis factor-␣ (TNF-␣), reactive oxygen species, proteases, and excitatory amino acids, which may induce neuronal degeneration.…”

Section: Discussionmentioning

confidence: 99%

Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy

Omri

Behar‐Cohen

Kozak

et al. 2011

The American Journal of Pathology

175

125

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Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase C (PKC ) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia. Up to 5 months, sparse microglia/macrophages were detected in the subretinal space, together with numerous pores in retinal pigment epithelial (

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Section: Discussionmentioning

confidence: 99%

Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy

Omri

Behar‐Cohen

Kozak

et al. 2011

The American Journal of Pathology

175

125

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“…In some studies, iNOS has been detected in retinal capillary endothelial cells in hyperglycaemia [6,40], whereas others have not detected it [4,5,43]. iNOS-mediated degeneration of retinal capillaries in diabetes is probably not initiated in capillary pericytes, since high glucose has been reported to decrease iNOS expression in retinal pericytes [44].…”

Section: Discussionmentioning

confidence: 99%

“…Upregulation of iNOS level has been found in retinas of experimental diabetic rodents and human patients in most studies [3][4][5][6]. The significance of this enzyme in the development of diabetic retinopathy has not yet been defined, but increased production of nitric oxide is at least closely associated with the development of retinopathy.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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Aims/hypothesis Diabetes results in the upregulation of the production of several components of the inflammatory response in the retina, including inducible nitric oxide synthase (iNOS). The aim of this study was to investigate the role of iNOS in the pathogenesis of the early stages of diabetic retinopathy using iNOS-deficient mice (iNos −/− ). Materials and methods iNos −/− mice and wild-type (WT; C57BL/6J) mice were made diabetic with streptozotocin or kept as non-diabetic controls. Mice were killed at different time points after the induction of diabetes for assessment of vascular histopathology, cell loss in the ganglion cell layer (GCL), retinal thickness, and biochemical and physiological abnormalities. Results The concentrations of nitric oxide, nitration of proteins, poly(ADP-ribose) (PAR)-modified proteins, endothelial nitric oxide synthase, prostaglandin E 2 , superoxide and leucostasis were significantly (p<0.05) increased in retinas of WT mice diabetic for 2 months compared with nondiabetic WT mice. All of these abnormalities except PARmodified proteins in retinas were inhibited (p<0.05) in diabetic iNos −/− mice. The number of acellular capillaries and pericyte ghosts was significantly increased in retinas from WT mice diabetic for 9 months compared with nondiabetic WT controls, these increases being significantly inhibited in diabetic iNos −/− mice (p<0.05 for all). Retinas from WT diabetic mice were significantly thinner than those from their non-diabetic controls, whereas diabetic iNos −/− mice were protected from this abnormality. We found no evidence of cell loss in the GCL of diabetic WT or iNos −/− mice. Deletion of iNos had no beneficial effect on diabetes-induced abnormalities on the electroretinogram.Conclusions/interpretation We demonstrate that the inflammatory enzyme iNOS plays an important role in the pathogenesis of vascular lesions characteristic of the early stages of diabetic retinopathy in mice.

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“…Peroxynitrite (ONOO Ϫ ), formed through the reaction of superoxide with NO, 9 is a potent oxidant that initiates both nitrosative and oxidative reactions that affect cellular proteins, lipids, and DNA. 9 In diabetic retinas, inflammatory cytokines, oxidized LDL, and hypoxia may induce iNOS, 23 which produces a large amount of NO. The over-production of NO not only provides an essential precursor for ONOO Ϫ generation, but also contributes to pericyte loss in diabetic retinopathy.…”

Section: Hog-ldl Increases No Production Inos Expression and 3-nitrmentioning

confidence: 99%

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

Zou

et al. 2011

The American Journal of Pathology

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The risk of diabetic retinopathy is associated with the presence of both oxidative stress and toxic eicosanoids. Whether oxidative stress actually causes diabetic retinopathy via the generation of toxic eicosanoids, however, remains unknown. The aim of the present study was to determine whether tyrosine nitration of prostacyclin synthase (PGIS) contributes to retinal cell death in vitro and in vivo. Exposure of human retinal pericytes to heavily oxidized and glycated LDL (HOG-LDL), but not native forms of LDL (N-LDL), for 24 hours significantly increased pericyte apoptosis, accompanied by increased tyrosine nitration of PGIS and decreased PGIS activity. Inhibition of the thromboxane receptor or cyclooxygenase-2 dramatically attenuated HOG-LDL-induced apoptosis without restoring PGIS activity. Administration of superoxide dismutase (to scavenge superoxide anions) or L-N G -nitroarginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) restored PGIS activity and attenuated pericyte apoptosis. In Akita mouse retinas, diabetes increased intraretinal levels of oxidized LDL and glycated LDL, induced PGIS nitration, enhanced apoptotic cell death, and impaired blood-retinal barrier function. Chronic administration of tempol, a superoxide scavenger, reduced intraretinal oxidized LDL and glycated LDL levels, PGIS nitration, and retina cell apoptosis, thereby preserving the integrity of blood-retinal barriers. In conclusion, oxidized LDL-mediated PGIS nitration and associated thromboxane receptor stimulation might be important in the initiation and progression of dia- Loss of pericytes from retinal microvessels is an important event in the early stage of diabetic retinopathy, which is associated with increased pericyte apoptosis. Although the mechanisms responsible for pericyte apoptosis remain unclear, several studies have shown associations between dyslipidemia and the severity of diabetic retinopathy.1,2 Specifically, elevated levels of triglycerides, low density lipoprotein (LDL), and apolipoprotein B, a principal lipoprotein component of LDL, have been associated with diabetic retinopathy.1 However, these associations are relatively weak, leading us to hypothesize that the key contribution of lipoproteins to the propagation of diabetic retinopathy is not through changes in their plasma levels but, rather, through extravasation via a disrupted blood-retinal barrier and subsequent modification by glycation and oxidation. In support of this model, we have demonstrated that oxidized LDL is present in the retina in diabetic humans in proportion to the severity of diabetic retinopathy, 3 and in cell culture studies we have shown that oxidized LDL has injurious effects on retinal pericytes. 4,5

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Expression of the inducible isoform of nitric oxide synthase in the retinas of human subjects with diabetes mellitus

Cited by 107 publications

References 34 publications

Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy

Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy

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

Tyrosine Nitration of Prostacyclin Synthase Is Associated with Enhanced Retinal Cell Apoptosis in Diabetes

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