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R. Hamilton, H. Zong, C. McVicar, P. Yong, L. Colhoun, T. A. Gardiner, A. W. Stitt; Advanced Glycation Endproducts (ages) Modulate Some but Not All Retinal Neuroglial Alterations During Diabetes With Links to a Pro-Inflammatory Phenotype. Invest. Ophthalmol. Vis. Sci. 2009;50(13):20. doi: https://doi.org/.
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Diabetes has profound effects on the neural retina and these abnormalities are linked to vasodegeneration during retinopathy. AGEs are known to promote pro-inflammatory responses in other diabetic complications. The current study sought to identify morphological and functional changes to the retinal neuroglia during diabetes and determine if AGE inhibition can prevent pathology.
4-month diabetic (streptozotozin induced) Sprague Dawley rats and non-diabetic controls were treated with the AGE-inhibitor pyridoxamine (PYR) for the duration of diabetes. Retina were excised and evaluated for neuroglial pathology. Muller cells and astrocytes were assessed using Glial Fibrillary Acidic Protein (GFAP), amacrine cells using Calretinin, and microglia identified using CD11b immunoreactivity. Thick retinal cryosections were imaged by Z stacks using confocal microscopy. Parallel in vitro studies were carried out using murine BV-2 microglial cells treated with AGE-modified proteins and examined for NFkB P65 nuclear translocation and nitric oxide (NO) release by the Greiss assay.
Diabetes was associated with induced GFAP expression in Muller glia and a decrease in the number of calretinin positive cells in the central retina (P<0.01). PYR treatment of diabetic rats had no significant effect on these parameters. The number of microglia showing a "resting" dendritic phenotype did not change during diabetes but the number of microglia with an activated (amoeboid) morphology and overall number of microglia was significantly increased in diabetic retina when compared to controls (P<0.01). PYR attenuated this microglial response (P<0.05). PYR also prevented a diabetes-associated increase in TNF-alpha mRNA expression (P<0.05). In vitro studies demonstrated that AGE-exposure of BV-2 cells caused transcriptional activation of NFkB and downstream NO release (P<0.01).
AGE formation in diabetic retinopathy is linked to enhanced microglial activation. Inhibition of AGE formation or limiting possible AGE-receptor activation pathways may prevent pro-inflammatory responses during diabetic retinopathy.
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