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The AGE-receptor in the pathogenesis of diabetic complications
1Mount Sinai School of Medicine, New York, NY 10029, USA. helen.vlassara@mssm.edu
Abstract:
Native glucose-derived glycation derivatives (advanced glycation end products, AGE) in vascular, renal and neuronal tissues contribute to organ damage. Glycation derivatives include a number of chemically and cell-reactive substances, also termed glycoxidation products or glycotoxins (GT). Cell-associated AGE-specific receptors (AGE-Rs), AGE-R1-3, RAGE, as well as the scavenger receptors ScR-II and CD-36 that are present on vascular, renal, hemopoietic, and neuronal/glial cells, serve in the regulation of AGE uptake and removal. AGE-Rs also modulate cell activation, growth-related mediators, and cell proliferation, consequently influencing organ structure/function. This occurs via oxidant stress triggered via receptor-dependent or -independent pathways, and leads to signal activation pathways, resulting in pro-inflammatory responses. In susceptible individuals, the AGE-R expression/function may be subject to environmental or gene-related modulation, which in turn may influence tissue-specific gene functions. In this context, altered expression and activity of AGE-R components has recently been found in both mouse diabetes models and humans with diabetic complications. Although several gene polymorphisms are detected in most AGE-R components, no significant correlation to diabetic complications has as yet been found. Further investigation is underway to define whether primary or secondary genetic links of pathogenic significance exist in this system. Various AGE-binding peptides or soluble receptors have emerged as potential sequestering agents for toxic AGEs as potential therapies for diabetic complications.
Insights
Advanced glycation end products (AGEs) contribute to organ damage. AGE receptors (AGE-Rs) regulate AGEs, and their altered expression is linked to diabetic complications, suggesting therapeutic potential.
Area of Science:
- Biochemistry and Molecular Biology
- Pathophysiology
- Endocrinology
Background:
- Advanced glycation end products (AGEs), derived from glucose, are implicated in vascular, renal, and neuronal tissue damage.
- Glycation derivatives, also known as glycoxidation products or glycotoxins, are chemically reactive substances.
- Cell-associated receptors, including AGE-specific receptors (AGE-Rs) and scavenger receptors, regulate AGE uptake and removal, influencing cellular functions and organ integrity.
Purpose of the Study:
- To investigate the role of AGE receptors (AGE-Rs) in the development of organ damage associated with AGE accumulation.
- To explore the connection between AGE-R expression/function and diabetic complications in both animal models and human subjects.
- To identify potential therapeutic strategies targeting AGEs and their receptors for managing diabetic complications.
Main Methods:
- Analysis of AGE-R expression and activity in mouse diabetes models and human diabetic patients.
- Investigation of AGE-R-mediated signaling pathways, including oxidant stress and pro-inflammatory responses.
- Examination of potential genetic modulations (e.g., gene polymorphisms) affecting AGE-R function in relation to diabetic complications.
Main Results:
- Altered expression and activity of AGE-R components were observed in mouse diabetes models and humans with diabetic complications.
- AGE-Rs modulate cell activation, growth mediators, and proliferation, influencing organ structure and function through receptor-dependent or -independent pathways.
- While gene polymorphisms in AGE-R components exist, no significant correlation with diabetic complications has been definitively established yet.
Conclusions:
- AGEs and their receptors play a significant role in organ damage, particularly in the context of diabetes.
- Dysregulation of AGE-R expression and function is associated with diabetic complications, highlighting their pathogenic relevance.
- AGE-binding peptides and soluble receptors show promise as therapeutic agents for sequestering toxic AGEs and treating diabetic complications.