Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of athe...

Advanced glycation end products: sparking the development of diabetic vascular injury.

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.

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Advanced Glycation End Products and Diabetic Complications

The multiligand receptors that form the focus of this Perspective series have expectedly diverse functions, often conforming to potential gaps in the host response to invading pathogens that are not effectively manned by adaptive immunity. For example, the macrophage scavenger receptor (type A) interacts with bacterial cell walls and enhances clearance of Gram-negative bacteria from the circulation (1). Similarly, the macrophage mannose receptor binds mannose-rich carbohydrates typical of many microorganisms, thereby promoting their cellular uptake and disposal (2). The present contribution to the series concerns a member of the immunoglobulin superfamily that differs from the above molecules in that all known ligands in its broad repertoire can be generated endogenously (3). This cell surface protein, called RAGE because it serves as a receptor for nonenzymatically glycated adducts termed “advanced glycation endproducts” (AGEs), also binds β-sheet fibrils characteristic of amyloid; proinflammatory cytokine–like mediators of the S100/calgranulin family; and amphoterin, a nuclear protein sometimes found in the ECM (Table ​(Table11).



Table 1

RAGE ligands and associated pathophysiologic states



Binding of these ligands to RAGE does not accelerate clearance or degradation but rather begins a sustained period of cellular activation mediated by receptor-dependent signaling. This is the first of several distinctive themes that have emerged from studies of RAGE. Other unusual features of the receptor include its ability to engage classes of molecules, rather than individual ligands, and its enhanced surface expression in environments rich in RAGE ligands. This last point is crucial, since it explains how upregulation of this receptor can contribute to an ascending spiral of RAGE-dependent cellular perturbation. Taken together, these features of RAGE allow the receptor to propagate cellular dysfunction in a number of pathophysiologically relevant situations, most often dictated by the formation and persistence of ligands in the tissues. As described below, these diverse situations range from the complications of diabetes and cellular perturbation in amyloidoses to immune and inflammatory responses and tumor cell behavior.

/pdf/the-multiligand-receptor-rage-as-a-progression-factor-4pw2t0726q.pdf

The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses

The Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin MEDIATION OF NEURITE OUTGROWTH AND CO-EXPRESSION OF RAGE AND AMPHOTERIN IN THE DEVELOPING NERVOUS SYSTEM

Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.

Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.

The extended interaction of aldoses with proteins or lipids results in nonenzymatic glycation and oxidation, ultimately forming AGEs, the presence of which in the plasma and vessel wall is associated with diabetic vascular complications. We show here that AGE albumin in the intravascular space interacts with the vessel wall via binding to an integral membrane protein, receptor for AGE (RAGE), a member of the immunoglobulin superfamily, resulting in clearance from the plasma and induction of interleukin 6 mRNA. Intravenously infused 125I-AGE albumin showed a rapid phase of plasma clearance with deposition in several organs. Rapid removal of 125I-AGE albumin from the plasma was prevented by administration of a soluble, truncated form of RAGE, which blocked binding of 125I-labeled AGE albumin to cultured endothelial cells and mononuclear phagocytes, as well as by pretreatment with anti-RAGE IgG. Ultrastructural studies with AGE albumin-colloidal gold conjugates perfused in situ showed that in murine coronary vasculature this probe was taken up by endothelial plasmalemmal vesicles followed by transport either to the abluminal surface or by accumulation in intracellular vesicular structures reminiscent of endosomes and lysosomes. Consequences of AGE-RAGE interaction included induction of interleukin 6 mRNA expression in mice. These data indicate that RAGE mediates the interaction of AGEs with the vessel wall, both for removal of these glycated proteins from the plasma and for changes in gene expression.

https://www.pnas.org/content/pnas/91/19/8807.full.pdf

Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins

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Receptor for advanced glycation end products (AGEs) has a central role in vessel wall interactions and gene activation in response to circulating AGE proteins