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T. K. Ali, S. Matragoon, B. A. Pillai, A. B. El-Remessy; ProNGF Mediates Diabetes-Induced Vascular Permeability and Retinal Neuronal Death. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1327.
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Diabetic retinopathy is characterized by blood-retinal barrier (BRB) breakdown and neurotoxicity. These pathologies are associated with increases in oxidative stress and proinflammatory cytokines. Accumulation of pro-neurotrophins, such as pro-nerve growth factor (proNGF), has been associated with oxidative stress in injured vascular and neuronal tissues. The purpose of this study is to elucidate the pro-inflammatory role of peroxynitrite in mediating diabetes-induced vascular permeability and neuronal death and to evaluate the protective effects of Atorvastatin.
Sprague Dawley rats were rendered diabetic using streptozotosin and treated with Atorvastatin (10mg/kg/day, oral) or peroxynitrite decomposition catalyst, FeTPPs (15mg/kg/day, IP). BRB breakdown was assessed by fluorescein-conjugated BSA. Neuronal cell death was determined by TUNEL assay in flat-mounted retinas. Nitrotyrosine and 4-hydroxynonenal (4-HNE) adducts were determined using Slot-Blot analysis. Expression of proNGF and activation of RhoA were determined by Western Blot and pull down assay. Post-mortem eye samples were obtained from the GA Eye Bank.
Experimental diabetes induced breakdown of the BRB and increased neuronal cell death. Diabetes increased accumulation of Pro-NGF in retinal Müller cells compared to controls. These effects were associated with increased nitrotyrosine and 4-HNE formation, Rho Kinase activation and NGF p75NTR receptor expression. Treatment of diabetic animals with Atorvastatin or FeTPPs reduced levels of peroxynitrite, proNGF and RhoA, restored BRB integrity and prevented neuronal cell death.
Diabetes-induced peroxynitrite formation stimulates proNGF accumulation and activates RhoA leading to BRB breakdown and retinal neurodegeneration. Normalizing peroxynitrite and RhoA activation using Atorvastatin or FeTPPs restores BRB integrity, reduces neurotoxicity, and prevents accumulation of proNGF in the diabetic retina. Taken together, these results suggests that inhibiting peroxynitrite or RhoA may be effective therapeutic targets in early diabetic retinopathy.
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