Involvement of the Toxic AGEs (TAGE)-RAGE System in the Pathogenesis of Diabetic Vascular Complications: A Novel Therapeutic Strategy

Abstract

Diabetic vascular complications are leading causes of acquired blindness, end-stage renal failure, a variety of neuropathies, and accelerated atherosclerosis, which may be involved in the disabilities and high mortality rates suffered by 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 (Glycer-AGEs), the predominant components of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, a growing body of evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic vascular complications. Therefore, the inhibition of TAGE formation, blockade of TAGE-RAGE interaction, and the suppression of RAGE expression or its downstream pathways are promising targets for therapeutic interventions against diabetic vascular complications. In this review, we discuss the pathophysiological role of the TAGE-RAGE-oxidative stress system and related therapeutic interventions for preventing the development and progression of diabetic vascular complications.

Effect of Moringa oleifera on advanced glycation end-product formation and lipid metabolism gene expression in HepG2 cells

“…Advanced glycation end-product (AGE) formation in the body involves non-enzymatic reactions between high blood glucose and free amino groups in proteins, lipids, and nucleic acids through a series of reactions forming Schiff bases and Amadori products (Sato et al, 2006;Takeuchi et al, 2010). AGE are products of both lipid peroxidation and glycoxidation reactions (Fu et al, 1996).…”

Macrophage Recognition of Toxic Advanced Glycosylation End Products through the Macrophage Surface-Receptor Nucleolin

“…Toxic AGEs have been demonstrated to play an important role in the pathogenesis of renal failure, arteriosclerosis, angiopathy, and retinopathy in diabetic patients. 4,6,7) Several AGE receptors have been identified on vascular endothelial cells, vascular smooth muscle cells, and monocyote/macrophage membranes, including receptor for advanced glycosylation end-products (RAGE), 8) galectin-3, 9) scavenger receptor A1/A2, [10][11][12][13] CD36, 14) scavenger receptor B1, 15) lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), 16) and link domain-containing scavenger receptor-1/2. 16) Among these receptors, RAGE, scavenger receptor A, and LOX-1 have been reported as toxic (GCA or GOA-derived) AGE receptors.…”

“…16) Among these receptors, RAGE, scavenger receptor A, and LOX-1 have been reported as toxic (GCA or GOA-derived) AGE receptors. 7,12,16) The abundance of receptors that recognize AGEs indicates that their clearance is an important function for macrophages. However, although macrophages recognize, phagocytose, and degrade AGEs, excessive levels of AGEs may lead to macrophage accumulation-induced foam-cell formation, resulting in arteriosclerosis.…”

Involvement of the TAGE-RAGE system in non-alcoholic steatohepatitis: Novel treatment strategies

“…Furthermore, in diabetes such binding is considered to be involved in the pathogenesis and worsening of angiopathic conditions [10][11][12][13][14][15][16] . In our previous study, the most abundant type of toxic AGEs (TAGE); i.e., glyceraldehyde-derived AGEs (Glycer-AGEs), were found to make a significant contribution to the development of angiopathic conditions in DM [17][18][19][20] . In addition, there is a growing consensus that TAGE-RAGE interactions affect gene expression, intracellular signaling, and the secretion of pro-inflammatory factors and induce reactive oxygen species (ROS) production in various cell types including hepatic stellate cells (HSC) and hepatocytes [21,22] .…”