Activation of Nuclear Factor-κB Induced by Diabetes and High Glucose Regulates a Proapoptotic Program in Retinal Pericytes

Romeo, G; Liu, Weihua; Asnaghi, Veronica; Kern, Timothy S.; Lorenzi, Mara

doi:10.2337/diabetes.51.7.2241

Cited by 366 publications

(322 citation statements)

References 39 publications

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“…Apoptosis could play a role in early pericyte dropout of diabetic retinopathy [9]. Mechanisms proposed to account for this phenomenon include rapid fluctuations of blood glucose, increased Bax expression during hyperglycaemia, aldose-reductase hyperactivity, increased AGE production and nuclear factor-kappa B activation [9,10]. Our results confirm that high glucose increases pericyte apoptosis and suggest that PKC inhibition could further amplify it.…”

Section: Discussionsupporting

confidence: 71%

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

et al. 2003

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Aims/hypothesis. Drop-out of capillary pericytes occurs early and selectively in diabetic retinopathy. High glucose concentrations decrease replication and increase apoptosis of cultured pericytes. Since glucose activates protein kinase C, we investigated the effects of modulating this intracellular mediator on replication, cell cycle and apoptosis of cultured bovine retinal pericytes. Methods. Pericytes cultured in 5.6 or 28 mmol/l glucose were exposed to a protein kinase C activator (phorbol 12-myristate 13-acetate) and/or a selective inhibitor of its β2 isoform (LY379196). Cells were counted after 7 days. Proliferation by the tetrazolium to formazan assay and DNA synthesis by 5-bromo-2′-deoxyuridine incorporation were measured at day 4. Cell cycle by flow cytometry and apoptosis by ELISA were assessed at day 2. Results. High glucose reduced pericyte replication and increased apoptosis. Protein kinase C activation increased proliferation, while inhibition of its β2 isoform decreased it. Cell cycle was accelerated by protein kinase C activation and delayed by inhibition. Apoptosis was enhanced by protein kinase C inhibition and reduced by activation. Conclusions/interpretation. Protein kinase C inhibition amplifies the anti-proliferative and pro-apoptotic effects of high glucose on cultured pericytes, whereas stimulation reduces apoptosis and promotes proliferation both in physiological glucose and high glucose. Protein kinase C inhibition, proposed for the treatment of diabetic macular edema and proliferative retinopathy, might accelerate pericyte dropout in earlier stages when these cells are still present in retinal capillaries. [Diabetologia (2003) 46:416-419]

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Section: Discussionsupporting

confidence: 71%

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

et al. 2003

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“…Moreover, we examined the nuclear translocation of the p65 subunit of NF-kB, a known stress response potentially leading to apoptosis of PCs. 21 At day 1 after ischemia/reperfusion, a significantly increased nuclear-to-cytoplasm ratio of p65 immunoreactivity was observed in PCs ( Figures 1I and 1J), suggesting early activation of the NF-kB pathway in CD13 þ PCs after ischemia.…”

Section: Loss Of Cd13 þ Capillary Pericytes and Cd31 þ Endothelium Afmentioning

confidence: 90%

Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

Fernández-Klett

Potas

Hilpert

et al. 2012

J Cereb Blood Flow Metab

208

249

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Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRb) þ and CD105 þ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRb þ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.

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“…9. Inappropriate regulation of nuclear factor kappa B (NF-κB) DNA binding has been observed in the retina in diabetes [17,[48][49][50], resulting in increased transcription of NF-κB-regulated gene products, including iNOS [51]. Inhibition of inflammatory pathways via inhibition of PARP [17], NF-κB [51], cyclooxygenase [52], intercellular adhesion molecule-1 [16] and now also of iNOS inhibits the diabetes-induced degeneration of retinal capillaries in experimental diabetic animals.…”

Section: Discussionmentioning

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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Activation of Nuclear Factor-κB Induced by Diabetes and High Glucose Regulates a Proapoptotic Program in Retinal Pericytes

Cited by 366 publications

References 39 publications

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

Effects of protein kinase C inhibition and activation on proliferation and apoptosis of bovine retinal pericytes

Early Loss of Pericytes and Perivascular Stromal Cell-Induced Scar Formation after Stroke

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

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