Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice

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/interpretationRage−/− 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.

Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice

“…68,69 One possible mechanism whereby ACE2 overexpression attenuates the diabetes-associated increase of macrophage/ microglial cells ( Figure 5) is attributable to the ability of Ang(1-7) to antagonize AGTR1s (which are expressed on microglia). AGTR1 blockade with valsartan effectively decreased microglial density in a rodent model of DR. 70 Consistent with our findings, McVicar et al 65 found a significant increase of F4/80 þ microglia in the retina when compared with nondiabetic controls, after 3 and 6 months of diabetes in mice. Similarly, Muther et al 71 observed a regular distribution of F4/80 þ in the healthy mouse retina.…”

“…These cells were increased in streptozotocin-control by approximately threefold to fourfold compared with nondiabetic or ACE2-treated diabetic, consistent with previous findings. 65,66 Also consistent with our findings (Figure 5), DR has generally been found to be associated with increased microglia number near retinal vasculature in the inner retinal layers and in the outer plexiform layer, 25,67 normally localizing anterior to the outer nuclear layer. 52 This organization within the ganglion cell layer is consistent with the finding, in individuals with DR, that microglia accumulate around regions of vascular damage 25 and that vascular lesions in the diabetic retina are nonuniform in distribution.…”

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond

“…Indirect evidence that the activation of Glo-1 might improve the neurovascular unit comes from studies using mice deficient in the receptor for AGEs (RAGE). McVicar et al [59] found that Rage (also known as Ager)-knockout mice accumulated less methylglyoxal in their retinas in association with a strong activation of Glo-1 and were protected against microglial activation and vasoregression, with a minor, non-significant effect on pericyte dropout. Beyond genetic control of Glo-1 activity, established drugs have shown Glo-1-modulating properties.…”

High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun

“…Advanced glycation end products account for many diabetes complications through their engagement to advanced glycosylation end productspecific receptor (AGER) (4)(5)(6). Inhibition of AGER is regarded as a therapeutic option to prevent diabetes complications (7). Despite an epidemiologic study that has demonstrated that AGER may be involved in liver injury and subsequent carcinogenesis (8), the exact roles of AGER in liver tumorigenesis are still unknown.…”