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Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes
Carmel M McVicar1, Micheal Ward, Liza M Colhoun
1Centre for Experimental Medicine, Queen's University Belfast, Belfast, BT12 6BA, Northern Ireland, UK.
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.
Insights
Mice lacking the receptor for advanced glycation end products (RAGE) showed reduced diabetic retinopathy. Inhibiting RAGE may offer a new treatment for this condition.
Area of Science:
- Ophthalmology
- Immunology
- Endocrinology
Background:
- The receptor for advanced glycation end products (RAGE) is implicated in inflammatory processes across various tissues.
- Diabetic retinopathy (DR) is a significant microvascular complication of diabetes, leading to vision loss.
Purpose of the Study:
- To investigate the role of RAGE in the development of diabetic retinopathy.
- To assess the therapeutic potential of RAGE inhibition in managing DR.
Main Methods:
- Diabetes was induced in wild-type and RAGE-deficient mice using streptozotocin.
- Retinal parameters including vasopermeability, leucostasis, microglial activation, and microvasculature changes were analyzed.
- Levels of methylglyoxal (MG) and the activity of glyoxalase I were measured.
Main Results:
- RAGE expression increased in wild-type diabetic mice retinas at 12 weeks.
- RAGE-deficient mice accumulated less MG and exhibited reduced retinal vasopermeability, leucostasis, and microglial activation.
- RAGE deficiency protected against retinal acellular capillary formation but not pericyte loss.
Conclusions:
- RAGE deficiency confers protection against key features of diabetic retinopathy, particularly those involving innate immune responses.
- Targeting RAGE presents a promising therapeutic strategy for preventing or treating diabetic retinopathy.
