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T.A. Gardiner, P. Canning, A.W. Stitt; Role of Advanced Glycation in Blood–Retinal Barrier Dysfunction During Diabetes . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1714.
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Breakdown of the inner blood retinal barrier (iBRB) occurs early in diabetes and may progress to sight–threatening macular oedema. In the present study, we examined the impact of advanced glycation endproducts (AGEs) on vasopermeability–related variables in the diabetic retina and retinal vasculature, including inter–endothelial cell tight junction (TJ) integrity and vascular endothelial growth factor (VEGF)/VEGF–receptor2 (VEGF–R2) expression. We also investigated the role of the AGE–receptor galectin–3 (G3) in AGE–mediated iBRB pathophysiology.
Diabetes was induced in C57Bl6 wild–type (WT) mice and in G3 –/– knockout mice using a single injection of streptozotocin. Blood glucose was monitored weekly and HbA1c + serum/tissue–AGE levels quantified at the end of the experiment. The diabetic groups were further divided and one group was treated with the AGE–inhibitor pyridoxamine (PM); separate groups of WT and G3–/– mice were maintained as non–diabetic controls. After two weeks of diabetes, iBRB integrity was assessed with the Evans blue assay and TJ protein distribution by occludin–1 immunolocalisation and confocal microscopy. Retinal VEGF and VEGF–R2 expression was quantified using real–time RT–PCR and ELISA.
HbA1c and the AGE adduct carboxy–methyl–lysine (CML) were significantly increased in all diabetic groups but only CML was lower in the PM–treated groups, consistent with the function of PM as an inhibitor of advanced glycation. WT diabetic mice showed significantly greater iBRB breakdown (p<0.03) coupled with higher VEGF and VEGF–R2 expression in comparison to controls (P<0.05, P<0.01). PM–treated diabetics showed normal iBRB parameters and significantly reduced diabetes–mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM–treated diabetics demonstrated a near–normal configuration. G3–/– mice showed significantly less diabetes–mediated iBRB dysfunction and gene expression changes than their WT counterparts.
The data suggest an AGE–mediated disruption of iBRB in the diabetic retina that correlates with increased VEGF/VEGF–R2 expression. Inhibition of AGE formation with pyridoxamine or genetic deletion of the AGE–receptor galectin–3 can effectively prevent diabetes–induced breakdown of the blood–retinal barrier.
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