Abstract
Aims/hypothesisThe receptor for AGEs (RAGE) is linked to proinflammatory pathology in a range of tissues. The objective of this study was to assess the potential modulatory role of RAGE in diabetic retinopathy.MethodsDiabetes was induced in wild-type (WT) and Rage −/− mice (also known as Ager −/− mice) using streptozotocin while non-diabetic control mice received saline. For all groups, blood glucose, HbA1c and retinal levels of methylglyoxal (MG) were evaluated up to 24 weeks post diabetes induction. After mice were killed, retinal glia and microglial activation, vasopermeability, leucostasis and degenerative microvasculature changes were determined.ResultsRetinal expression of RAGE in WT diabetic mice was increased after 12 weeks (p < 0.01) but not after 24 weeks. Rage −/− mice showed comparable diabetes but accumulated less MG and this corresponded to enhanced activity of the MG-detoxifying enzyme glyoxalase I in their retina when compared with WT mice. Diabetic Rage −/− mice showed significantly less vasopermeability, leucostasis and microglial activation (p < 0.05–0.001). Rage −/− mice were also protected against diabetes-related retinal acellular capillary formation (p < 0.001) but not against pericyte loss.Conclusions/interpretation Rage −/− in diabetic mice is protective against many retinopathic lesions, especially those related to innate immune responses. Inhibition of RAGE could be a therapeutic option to prevent diabetic retinopathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3523-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Diabetic retinopathy is typified by breakdown of the blood– retina barrier (BRB), loss of capillary pericytes and endothelium, microaneurysm formation, neuronal/glial dysfunctionDiabetologia (2015) 58:1129–1137 and progressive ischaemia in the early stages [1]
Blood glucose was significantly increased in the diabetic mice of both WT and Rage−/− mice at 24 weeks of diabetes (ESM Fig. 1d)
MG and its detoxification in the diabetic retina Compared with non-diabetic WT controls, Rage mRNA expression in the retina was increased after 12 weeks of diabetes ( p
Summary
Diabetic retinopathy is typified by breakdown of the blood– retina barrier (BRB), loss of capillary pericytes and endothelium, microaneurysm formation, neuronal/glial dysfunctionDiabetologia (2015) 58:1129–1137 and progressive ischaemia in the early (non-proliferative) stages [1]. Even in the early stages of disease inflammatory pathology manifests as activation of resident and infiltrating immune cells, abnormal expression of proinflammatory cytokines, upregulation of adhesion molecules and leucostasis in retinal capillaries [2]. This relatively nonspecific and sustained response to diabetes-related cell injury seems to be driven, at least in part, by microglia and Müller glia acting as the main resident innate immune cells of the retina. The complex interplay of PRRs in the diabetic retina remains poorly understood there has been recent attention given to RAGE and its role in diabetic retinopathy [4,5,6]
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