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Advanced glycation end products, their receptors and diabetic angiopathy
J L Wautier1, P J Guillausseau
1Laboratoire de biologie vasculaire et cellulaire, UFR Lariboisière St Louis, Université Paris 7 Denis-Diderot. wautier@ints.fr
Abstract:
The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established by intervention studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. This review focuses on the consequences of hyperglycemia on the formation of advanced glycation end-products (AGEs), and on the role of AGEs and of their specific receptors (RAGE) in the functional and anatomical alterations of the vascular wall. AGEs are formed during the Maillard reaction by the binding of aldoses on free NH(2) groups of proteins, which, after a cascade of molecular rearrangements, result in molecules of brown color and specific fluorescence. Experimental studies have indicated that the binding of AGEs to RAGE activates cells, particularly monocytes and endothelial cells. Activated endothelial cells produce cytokines, and express adhesion molecules and tissue factor. The role of AGEs in increased oxidative stress, and in the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The microvascular retinal, glomerular and nerve lesions induced by experimental diabetes in animals are prevented by an inhibitor of AGEs formation, aminoguanidine. The administration in diabetic animals of recombinant RAGE, which hinders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesions. These data suggest a central role of AGEs and RAGE in the development of chronic complications of diabetes.
Insights
Chronic hyperglycemia drives diabetic complications by forming advanced glycation end-products (AGEs). Targeting AGEs and their receptor (RAGE) pathways may prevent vascular damage and neuropathy in diabetes.
Area of Science:
- Biochemistry
- Cell Biology
- Endocrinology
Background:
- Chronic hyperglycemia is a known risk factor for diabetic microvascular complications and neuropathy.
- The precise biochemical and cellular mechanisms linking high blood glucose to vascular damage are not fully understood.
Purpose of the Study:
- To review the role of advanced glycation end-products (AGEs) and their receptor (RAGE) in the vascular alterations associated with diabetes.
- To discuss the impact of hyperglycemia on AGE formation, oxidative stress, and vascular dysfunction.
Main Methods:
- Review of experimental studies investigating AGEs, RAGE, and their effects on vascular cells and function.
- Analysis of data from studies using AGE formation inhibitors (e.g., aminoguanidine) and RAGE blockers in diabetic animal models.
Main Results:
- Hyperglycemia promotes the formation of AGEs through the Maillard reaction.
- AGEs binding to RAGE activates monocytes and endothelial cells, leading to cytokine production and adhesion molecule expression.
- AGEs contribute to oxidative stress and impaired vascular tone, partly via reduced nitric oxide bioavailability.
- Inhibition of AGE formation or AGE-RAGE interaction prevented microvascular lesions and hyperpermeability in experimental diabetes.
Conclusions:
- AGEs and RAGE play a critical role in the pathogenesis of diabetic microvascular complications.
- Targeting AGEs and RAGE represents a potential therapeutic strategy for managing long-term diabetic complications.