Advanced glycation end products (AGEs) are a heterogenous group of molecules formed during a non-enzymatic reaction between proteins and sugar residues. Recently, AGEs and their receptor (receptor for AGEs; RAGE) play a central role in the pathogenesis of cardiovascular disease (CVD), which accounts for disability and high mortality rate in patients with diabetes. AGEs initiate diabetic micro- and macrovascular complications through the structural modification and functional alteration of the extracellular matrix proteins as well as intracellular signaling molecules. Engagement of RAGEs with AGEs elicits intracellular reactive oxygen species (ROS) generation and subsequently activates mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NF-κB) signaling, followed by production of several inflammatory and/or profibrotic factors such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1), thereby being involved in the progression of atherosclerosis. Administration of soluble form of RAGE (sRAGE) could work as a decoy receptor for AGEs and might inhibit the binding of AGEs to RAGE, preventing the development and progression of atherosclerosis in animal models. Furthermore, AGEs/high mobility group box-1 (HMGB-1)-RAGE interaction is involved in heart failure, abdominal aortic aneurysm (AAA) and vascular calcification as well. Thus, blockade of the AGEs/HMGB-1-RAGE system may be a promising therapeutic target for preventing diabetes- and/or age-related CVD. We review here the pathological role of the AGEs/HMGB-1-RAGE system in various types of CVD.

Diabetic nephropathy is the most common cause of end-stage renal disease in the world, and accounts for a significant increase in morbidity and mortality in patients with diabetes. Therapeutic options such as strict blood pressure and/or glycemic control are effective for preventing the development and progression of diabetic nephropathy, but the number of diabetic patients on hemodialysis is still increasing. Therefore, a novel therapeutic strategy that could halt the progression of diabetic nephropathy should be developed. Advanced glycation end products (AGEs) are heterogeneous cross-linked sugar-derived proteins which could accumulate in glomerular basement membrane, mesangial cells, endothelial cells, and podocytes in patients with diabetes and/or end-stage renal failure. AGEs are thought to be involved in the pathogenesis of diabetic nephropathy via multifactorial mechanisms such as oxidative stress generation and overproduction of various growth factors and cytokines. Further, recently, the cross-talk between AGEs and the renin-angiotensin system (RAS) has been proposed to participate in diabetic nephropathy. In addition, activation of the RAS elicits ROS generation and subsequently stimulates growth factor and cytokine production by kidney cells as well. These observations suggest that combination therapy with inhibitors of the RAS and blockers of the AGEs formation and/or their downstream pathway may be a novel therapeutic option for preventing diabetic nephropathy. In this paper, we review the role of AGEs and their receptor system in the pathogenesis of diabetic nephropathy. We further discuss here the cross-talk between AGEs and the RAS in the development and progression of diabetic nephropathy.

Advanced glycation end products (AGEs) consist of heterogenous group of macroprotein derivatives, which are formed by non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids, and whose process has progressed at an accelerated rate under diabetes. Non-enzymatic glycation and cross-linking of protein alter its structural integrity and function, contributing to the aging of macromolecules. Furthermore, engagement of receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes proliferative, inflammatory, and fibrotic reactions in a variety of cells. Indeed, accumulating evidence has suggested the active involvement of accumulation of AGEs in diabetes-associated disorders such as diabetic microangiopathy, atherosclerotic cardiovascular diseases, Alzheimer’s disease and osteoporosis. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins, gut hormones secreted from the intestine in response to food intake, both of which augment glucose-induced insulin release, suppress glucagon secretion, and slow gastric emptying. Since GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4), inhibition of DPP-4 and/or DPP-4-resistant GLP-1 analogues have been proposed as a potential target for the treatment of diabetes. Recently, DPP-4 has been shown to cleave multiple peptides, and blockade of DPP-4 could exert diverse biological actions in GLP-1- or GIP-independent manner. This article summarizes the crosstalk between AGEs-RAGE axis and DPP-4-incretin system in the development and progression of diabetes-associated disorders and its therapeutic intervention, especially focusing on diabetic vascular complications.

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight-week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with those in C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2′-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor, and type IV collagen both in the kidney of KKAy/Ta mice and in AGE-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy.

Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice. Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone. Compared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice. Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.

Advanced glycation end products (AGEs) and receptor RAGE interaction contribute to endothelial cell damage in diabetes. Several thrombogenic abnormalities are also involved in diabetic vascular complications. However, the pathological role of thrombin and protease-activated receptor-1 (PAR-1) system in AGE-induced endothelial cell (EC) damage remains unclear. In this study, we investigated the effects of rivaroxaban, an inhibitor of factor Xa on 3% citrated human plasma-evoked reactive oxygen species (ROS) generation and RAGE, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) gene expression in AGE-exposed ECs. We further examined whether FR171113, an inhibitor of PAR-1 blocked the plasma-induced EC damage and if AGEs increased PAR-1 expression in ECs. Human citrated plasma stimulated ROS generation and RAGE, MCP-1 and ICAM-1 expression in ECs, all of which were potentiated by the treatment with AGEs. Rivaroxaban or FR171113 significantly inhibited these derangements in plasma- or plasma plus AGE-exposed ECs. Moreover, AGEs significantly increased the PAR-1 levels in ECs. The present study suggests that citrated plasma could induce oxidative and inflammatory reactions in ECs via the activation of thrombin-PAR-1 system and that AGEs could potentiate the plasma-evoked EC damages via up-regulation of PAR-1. Blockade of the crosstalk between AGE-RAGE axis and coagulation system by rivaroxaban might be a novel therapeutic target for thromboembolic disorders in diabetes.