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Mol Vis ; 19: 1047-59, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23734074

RESUMO

PURPOSE: Hyperglycemia activates several metabolic pathways, including the hexosamine biosynthetic pathway. Uridine diphosphate N-acetylglucosamine (GlcNAc) is the product of the hexosamine biosynthetic pathway and the substrate for O-linked GlcNAc (O-GlcNAc) modification. This modification affects a wide range of proteins by altering their activity, cellular localization, and/or protein interactions. However, the role O-GlcNAcylation may play in normal postnatal retinal vascular development and in the ocular complications of diabetes, including diabetic retinopathy, requires further investigation. METHODS: The total levels of O-GlcNAc-modified proteins were evaluated by western blot analysis of lysates prepared from retinas obtained at different days during postnatal retinal vascularization and oxygen-induced ischemic retinopathy. Similar experiments were performed with retinal lysate prepared from diabetic Ins2(Akita/+) mice with different durations of diabetes and retinal vascular cells cultured under various glucose conditions. The localization of O-GlcNAc-modified proteins in the retinal vasculature was confirmed by immunofluorescence staining. The impact of altered O-GlcNAcylation on the migration of retinal vascular cells was determined using scratch wound and transwell migration assays. RESULTS: We detected an increase in protein O-GlcNAcylation during mouse postnatal retinal vascularization and aging, in part through the regulation of the enzymes that control this modification. The study of the diabetic Ins2(Akita/+) mouse retina showed an increase in the O-GlcNAc modification of retinal proteins. We also observed an increase in retinal O-GlcNAcylated protein levels during the neovascularization phase of oxygen-induced ischemic retinopathy. Our fluorescence microscopy data confirmed that the alterations in retinal O-GlcNAcylation are similarly represented in the retinal vasculature and in retinal pericytes and endothelial cells. Particularly, the migration of retinal pericytes, but not retinal endothelial cells, was attenuated by increased O-GlcNAc modification. CONCLUSIONS: The O-GlcNAc modification pattern changes during postnatal retinal vascular development and neovascularization, and its dysregulation under hyperglycemia and/or ischemia may contribute to the pathogenesis of the diabetic retinopathy and retinal neovascularization.


Assuntos
Acetilglucosamina/metabolismo , Retinopatia Diabética/fisiopatologia , Proteínas do Olho/metabolismo , Neovascularização Fisiológica , Processamento de Proteína Pós-Traducional , Retina/metabolismo , Vasos Retinianos/fisiopatologia , Envelhecimento/patologia , Animais , Animais Recém-Nascidos , Movimento Celular/efeitos dos fármacos , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Glucose/farmacologia , Glicosilação/efeitos dos fármacos , Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica/efeitos dos fármacos , Pericitos/efeitos dos fármacos , Pericitos/metabolismo , Pericitos/patologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Retina/crescimento & desenvolvimento , Retina/patologia , Retina/fisiopatologia , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/crescimento & desenvolvimento , Vasos Retinianos/patologia
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