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Carmel McVicar, Micheal Ward, Liza Colhoun, Darren Conway, Hans-Peter Hammes, Alan Stitt; Role of the Receptor for Advanced Glycation Endproducts (RAGE) in retinal vasodegenerative pathology during diabetes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2706.
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The receptor for advanced glycation end-products (RAGE) is a multi-ligand binding receptor linked to pro-inflammatory pathology in a range of tissues. The study aim was to assess the role of RAGE in microglial activation and retinal microvascular pathology during diabetic retinopathy.
Streptozotocin (STZ)-induced diabetes was maintained in wild-type (WT), C57BL/6 mice and RAGE-/- mice for 2, 12 and 24 weeks (n=6/group). Age-match non-diabetics were used as controls. At sacrifice, the retina was assessed for microglial activation, pro-inflammatory cytokine mRNA expression and degenerative microvasculature changes. The leukostasis assay was performed on mice which had been diabetic for 2 weeks.
In the diabetic WT mice, glial fibrillary acidic protein (GFAP) was hyper-expressed in the Müller cells. S100B was increased in these cells during diabetes. These responses appeared diminished in RAGE-/- diabetic mice. Both 12 and 24 weeks diabetes increased the numbers and activation state of microglia in the retina concomitant with increased retinal mRNA expression of TNFalpha and IL-1beta (P<0.01-0.001). These diabetes-mediated inflammatory responses were significantly blunted in diabetic RAGE-/- mice. In the absence of RAGE, there was prevention of acellular capillary formation during diabetes (p<0.001). Leukostasis in the retinal vasculature was increased in WT diabetic mice although this was diminished in RAGE-/- diabetic mice.
RAGE plays a key role in diabetes-mediated inflammatory responses in the retina. Inhibition of RAGE activation as diabetes progresses could be an important therapeutic option to prevent glial and microvascular pathology during diabetic retinopathy in patients.
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