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

Carmel M. McVicar, Michael Ward, Liza M. Colhoun, Jasenka Guduric-Fuchs, Angelika Bierhaus, Thomas Fleming , Andreas Schlotterer, Mathias Kolibabka, Hans-Peter Hammes , Mei Chen, Alan W. Stitt

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Abstract

Aims/hypothesis
The 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.
Methods
Diabetes 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. 

Results
Retinal 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.
Original languageEnglish
Pages (from-to)1129-37
Number of pages9
JournalDiabetologia
Volume58
Issue number5
Early online date17 Feb 2015
DOIs
Publication statusPublished - May 2015

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