Purchase this article with an account.
T. K. Ali, S. Matragoon, G. I. Liou, A. B. El-Remessy; Peroxynitrite Mediates Diabetes-Induced Retinal Neuronal Death via Tyrosine Nitration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4978.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Our previous studies have shown retinal neuronal cell death is correlated with increases in oxidative stress and tyrosine nitration in experimental diabetes and in NMDA-neurotoxicity model. These studies suggest a key role of peroxynitrite in mediating neural cell death. However, the causal role of peroxynitrite in diabetes-induced neurodegeneration has not been elucidated. Neurotrophins, such as nerve growth factor (NGF), regulate the survival of retinal neuronal cells through binding to the survival tyrosine kinase receptors (Trk). This study is undertaken to test the neuroprotective effects of the specific peroxynitrite decomposition catalyst, FeTPPs, and to elucidate the mechanism by which tyrosine nitration inhibits NGF-mediated neuronal cell survival.
Sprague Dawley rats were rendered diabetic by a single injection of 65 mg/kg of streptozotosin. Treatment with FeTPPs (15 mg/Kg/day, I.P) did not alter body weight or blood glucose level. After 4 weeks of diabetes, retinal cell death was determined by terminal dUTP nick-end labeling assay both in flat mounted retinas and in frozen retinal sections. Lipid peroxidation was determined using MDA assay and nitrotyrosine was determined using immunofluorescence. Expression of TrkA, its tyrosine nitration and phosphorylation were determined by immunoprecipitation and Western Blot analysis.
Experimental diabetes induced significant increases in retinal neuronal cell death that was associated with increases in retinal nitrotyrosine and lipid peroxidation. These effects were associated with increased TrkA tyrosine nitration and decreased TrkA phosphorylation. Treatment of diabetic animals with FeTPPs blocked retinal nitrotyrosine formation and lipid peroxidation. FeTPPs also blocked TrkA tyrosine nitration, restored its phosphorylation and prevented neuronal cell death.
Inhibiting peroxynitrite formation reduces neurotoxicity, blocks tyrosine nitration and restores activation of the survival TrkA receptor in the diabetic retina. These data demonstrate that peroxynitrite and tyrosine nitration play a key role in diabetes-induced neurodegeneration. Treatments that inhibit peroxynitrite or tyrosine nitration may be effective therapeutic targets in early diabetic retinopathy.
This PDF is available to Subscribers Only