Abstract
Purpose:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Keywords: 499 diabetic retinopathy