Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy
ABSTRACT Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic derangements. In this review, we discuss the molecular mechanisms of diabetic retinopathy and nephropathy, especially focusing on advanced glycation end products (AGEs) and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in diseases, including diabetic microangiopathy, will be discussed in the next review article.
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- "RAGE mediates physiological and pathological effects through interaction with a diverse set of ligands, which remarkably , are each associated with a specific disease. The first identified RAGE ligand was advanced glycation end products (AGEs), which form by nonenzymatic glycation of proteins and lipids and accumulate as a result of normal aging and inflammatory processes, particularly in diabetes (Yamagishi et al., 2003). RAGE is up-regulated in Alzheimer disease, and soluble amyloid-b has been shown to bind to the receptor inducing oxidative stress in neurons and the production of proinflammatory cytokines in microglia (Yan et al., 2003). "
ABSTRACT: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling events upon binding of a variety of ligands, such as glycated proteins, amyloid-β, HMGB1, and S100 proteins. The X-ray crystal structure of the VC1 ligand-binding region of the human RAGE ectodomain was determined at 1.85 Å resolution. The VC1 ligand-binding surface was mapped onto the structure from titrations with S100B monitored by heteronuclear NMR spectroscopy. These NMR chemical shift perturbations were used as input for restrained docking calculations to generate a model for the VC1-S100B complex. Together, the arrangement of VC1 molecules in the crystal and complementary biochemical studies suggest a role for self-association in RAGE function. Our results enhance understanding of the functional outcomes of S100 protein binding to RAGE and provide insight into mechanistic models for how the receptor is activated.Structure 10/2010; 18(10):1342-52. DOI:10.1016/j.str.2010.05.017 · 6.79 Impact Factor
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- "There is a growing body of evidence to suggest that continuous hyperglycemia under diabetic conditions enhances the formation of AGEs, senescent macroprotein derivatives , through nonenzymatic glycation (called the " Maillard reaction " ). There is also accumulating evidence that the binding of the receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes inflammatory and/or thrombogenic responses in various types of cells, thus participating in the development and progression of diabetic angiopathies         . Recently, we demonstrated that glyceraldehyde-derived AGEs (Glycer- AGEs), the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients   . "
ABSTRACT: Diabetic complications are a leading cause of acquired blindness, end-stage renal failure, and accelerated atherosclerosis, which are associated with the disabilities and high mortality rates seen in diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, recent evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications. In this paper, we discuss the pathophysiological role of the TAGE-RAGE system in the development and progression of diabetic retinopathy.Journal of Ophthalmology 06/2010; 2010:170393. DOI:10.1155/2010/170393 · 1.94 Impact Factor
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- "AGEs play an important causative role in the pathogenesis of diabetic vascular complications, such as diabetic retinopathy (Yamagishi et al. 1997; Lander et al. 1997; Stitt et al. 2005). There are several potential explanations for the effects of AGEs and RAGEs on endothelial cells, pericytes, smooth muscle cells, dendritic cells, monocyte cells and infiltrating mononuclear phagocytes in the diabetic vasculature (Hori et al. 1995; Sakata et al. 2000; Yamagishi et al. 2003). AGEs are known to induce angiogenic effects through multiple survival signals (Triens et al. 2001; Goldin et al. 2006), including the secretion of VEGF, which exerts an autocrine action in a variety of endothelial cells and other cell types. "
ABSTRACT: The purpose of this study was to investigate the effect of pigment epithelium-derived factor (PEDF) on the signaling cascade in porcine retinal endothelial cells (PRECs) related to angiogenesis induced by advanced glycation end-products (AGEs). Endothelial cells were isolated from porcine retina by the enzymatic method. Immunocytochemistry was performed to confirm the identity of PRECs. The effect of AGEs and PEDF on cell viability was determined by the MTT assay. An in vitro wound-scratch assay was performed to study the migration of ECs, and in vitro tube formation was assessed by the on-gel assay system using an extracellular matrix. Inhibitor assays were carried out using LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, and Akt inhibitor VIII. PI3K/Akt activity was assessed by transient transfection and western blot analysis. Induction of apoptosis by PEDF was determined by caspase-3 colorimetric assay and DNA fragmentation analysis. Treatment of PRECs with AGE-bovine serum albumin (AGE-BSA) significantly increased the cell proliferation, migration and tube formation compared to non-glycated BSA. AGE-BSA mediates cell survival via the PI3K/Akt/FKHR-dependent pathway as evidenced by transient transfection and western blot analyses. Furthermore, PEDF significantly inhibited the proliferation, migration and tube formation, both in the presence and absence of AGE-BSA in PRECs. PEDF inactivated the AGE-BSA-induced PI3K/Akt/FKHR activity and induced apoptosis via caspase-3. The results reveal that PEDF inhibits AGE-BSA-induced PI3K/Akt/FKHR signaling in PRECs. Thus, PEDF has potent anti-angiogenic effects against AGE-induced angiogenesis and is suggested to be a promising molecule for the treatment of diabetic retinopathy.Life sciences 10/2009; 85(21-22):719-31. DOI:10.1016/j.lfs.2009.09.015 · 2.30 Impact Factor