Selective inhibition by grape seed proanthocyanidin extracts of cell adhesion molecule expression induced by advanced glycation end products in endothelial cells

The interaction of advanced glycation end products (AGE) with their cell surface receptors for AGEs (RAGE) has been causally implicated in the pathogenesis of diabetic vascular complications and has been shown to stimulate cell adhesion molecule expression in endothelial cells via induction of reactive oxygen species (ROS). Alternatively, grape seed proanthocyanidin extracts (GSPE), which are naturally occurring polyphenolic compounds, have been reported to possess potent radical scavenging and antioxidant properties and to display significant cardiovascular protective action. In this study, we investigated whether GSPE could inhibit AGE-induced cell adhesion molecule expression through interference with ROS generations in human umbilical vein endothelial cells. AGE-modified bovine serum albumin (AGE-BSA) was prepared by incubating BSA with a high concentration of glucose. Stimulation of cultured human umbilical vein endothelial cells with 200 microg/mL of AGE-BSA significantly enhanced intracellular ROS formation and subsequently upregulated the expression of vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM-1), whereas both unmodified BSA and GSPE alone were without effect. However, preincubation of different concentrations of GSPE markedly downregulated AGE-BSA-induced VCAM-1 expression at the surface protein and mRNA level in a concentration-dependent manner, but the increased ICAM-1 expression was not affected by GSPE treatment. Meanwhile, the inhibition by GSPE of intracellular ROS generation was also observed at defined time periods. These results demonstrate that GSPE can inhibit the enhanced VCAM-1 expression but not ICAM-1 in AGE-exposed endothelial cells by suppressing ROS generation. Hence, GSPE may have therapeutic potential in the prevention and treatment of vascular complications in patients with diabetes.     

Nifedipine inhibits gene expression of receptor for advanced glycation end products (RAGE) in endothelial cells by suppressing reactive oxygen species generation

Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of diabetic vascular complications. Indeed, AGEs elicit oxidative stress generation in vascular wall cells through an interaction with their receptor (RAGE), thus playing an important role in vascular inflammation and altered gene expression of growth factors and cytokines. We have previously shown that nifedipine, one of the most popular dihydropyridine-based calcium antagonists, blocked tumor necrosis factor-alpha-induced monocyte chemoattractant protein-1 expression in endothelial cells (ECs) through its antioxidative properties. However, the effects of nifedipine on AGE-exposed ECs remain to be elucidated. In this study we investigated whether nifedipine could inhibit the AGE-induced reactive oxygen species (ROS) generation and subsequent RAGE gene expression in human umbilical vein endothelial cells (HUVEC). Nifedipine completely inhibited AGE-induced ROS generation in HUVEC. Furthermore, nifedipine was found to prevent up-regulation of RAGE mRNA levels in AGE-exposed HUVEC. These results demonstrate that nifedipine can inhibit RAGE overexpression in AGE-exposed ECs by suppressing ROS generation. Our present study suggests that nifedipine may have therapeutic potential in the treatment of patients with AGE-related disorders such as diabetic vascular complications.     

Grape seed proanthocyanidin extracts inhibit vascular cell adhesion molecule expression induced by advanced glycation end products through activation of peroxisome proliferators-activated receptor gamma

Although evidence has shown that grape seed proanthocyanidin extracts (GSPE) can selectively inhibit cell adhesion molecule expression induced by advanced glycation end products (AGEs), the underlying molecular mechanism has not been extensively characterized. To study the antiinflammation mechanism of GSPE, we investigated the effect of GSPE on Von Willebrand factor (vWF) content and the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by AGEs and the effect of GSPE on peroxisome proliferators-activated receptor gamma (PPAR gamma) and receptor for AGEs (RAGE) expression in human umbilical vein endothelial cells (HUVEC). HUVEC were preincubated with or without GSPE of different concentrations (10 mg/L, 50 mg/L, and 100 mg/L) for 4 hours before being treated with 200 mg/L AGEs or unmodified bovine serum albumin (BSA) for 24 hours. The expression of RAGE and PPAR gamma was investigated by Western blot. VCAM-1 expression was measured by flow cytometry and vWF content by enzyme-linked immunosorbent assay (ELISA). Results showed that GSPE significantly inhibited the expression of VCAM-1 in HUVEC and reduced the content of vWF in culture fluid induced by AGEs in a dose-dependent manner. AGEs activated the expression of RAGE and inhibited PPAR gamma expression in HUVEC, whereas GSPE inhibited the expression of RAGE through activation of PPAR gamma in HUVEC simultaneously. These findings indicated that GSPE inhibited the cell inflammatory factor expression and protected the function of endothelial cell through activation of PPAR gamma expression and inhibition of RAGE expression.     

Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury

Advanced glycation end products (AGEs) and their receptor (RAGE) axis contributes to diabetic nephropathy. An oral hypoglycemic agent, metformin may have a potential effect on the inhibition of glycation reactions. Further, since a pathophysiological crosstalk between renin-angiotensin system (RAS) and AGEs-RAGE axis is involved in diabetic nephropathy, it is conceivable that metformin and irbesartan additively could protect against the AGEs-RAGE-induced tubular cell injury. In this study, we addressed the issues. Metformin dose-dependently inhibited the formation of AGEs modification of bovine serum albumin (BSA). Compared with AGEs-modified BSA prepared without metformin (AGEs-MF0), those prepared in the presence of 30 mM or 100 mM metformin (AGEs-MF30 or AGEs-MF100) significantly reduced RAGE mRNA level, reactive oxygen species (ROS) generation, apoptosis, monocyte chemoattractant protein-1 and transforming growth factor-β mRNA level in tubular cells. Irbesartan further inhibited the harmful effects of AGEs-MF0 or AGEs-MF30 on tubular cells. Our present study suggests that combination therapy with metformin and irbesartan may have therapeutic potential in diabetic nephropathy; it could play a protective role against tubular injury in diabetes not only by inhibiting AGEs formation, but also by attenuating the deleterious effects of AGEs via down-regulating RAGE expression and subsequently suppressing ROS generation.     

替米沙坦对AGEs诱导人内皮细胞表达VCAM-1及MCP-1的作用和机制

目的 通过观察替米沙坦对晚期糖基化终末产物（AGEs）诱导的人脐静脉内皮细胞表达血管细胞黏附因子-1（VCAM-1）和单核细胞趋化蛋白-1（MCP-1）的影响,研究替米沙坦对AGEs所致动脉粥样硬化（AS）的干预作用和机制。方法 采用胶原酶消化法获取人脐静脉内皮细胞,分为4组：空白对照组,牛血清白蛋白（BSA）对照组,AGEs诱导组（10^-4~10^-1mg/mL）,AGEs+替米沙坦组（1、10、100 nmol/L）。活性氧检测试剂盒检测及倒置荧光显微镜观察细胞内活性氧含量,RT-PCR检测VCAM-1、MCP-1及晚期糖基化终末产物受体（RAGE）的mRNA。结果 AGEs组人内皮细胞内活性氧荧光强度增强,替米沙坦干预后降低;AGEs呈浓度依赖性地增强人内皮细胞对VCAM-1和MCP-1基因的转录,与空白对照组相比,AGEs（10^-4mg/mL）组VCAM-1和MCP-1 mRNA表达水平显著增高（0.24±0.01 vs 0.07±0.02;0.25±0.01 vs 0.18±0.03,P<0.05）;替米沙坦呈浓度依赖性地抑制人内皮细胞对VCAM-1和MCP-1基因的转录,与AGEs诱导组相比,替米沙坦（10 nmol/L）组人内皮细胞的VCAM-1和MCP-1基因转录水平显著降低（0.23±0.01 vs 0.85±0.11;0.62±0.10 vs 1.05±0.04,P<0.05）;与AGEs诱导组相比,替米沙坦（1 nmol/L）组人内皮细胞RAGE基因表达水平显著降低（0.64±0.03 vs 1.18±0.10,P<0.05）。结论 AGEs增强人内皮细胞表达VCAM-1和MCP-1;替米沙坦可能通过抑制RAGE表达来抑制AGEs诱导的人内皮炎性损伤。     

Inhibitory effects of Terminalia chebula extract on glycation and endothelial cell adhesion

Terminalia chebula Retz. has been used in India for a long time to treat many diseases, and its extract was reported to have antidiabetic activity in vivo. In this study, T. chebula methanolic extract (TCE) containing 2.7 % chebulic acid was evaluated for its preventive effects against the formation of advanced glycation end products (AGEs) and endothelial cell dysfunction. When the effects of TCE on AGE formation and on protein crossing-linking by glycation with D-threose and lens crystallines were examined, TCE showed inhibitory activity in a dose-dependent manner, and the concentration of 1000 μg/mL presented an activity similar to that of 5 mM aminoguanidine as a positive control. Upon investigating the protective activity of TCE against AGE-induced vascular endothelium dysfunction, human umbilical vein endothelial cells (HUVEC) incubated with 100 μg/mL of AGEs had significantly enhanced reactive oxygen species (ROS) formation, whereas the treatment of T. chebula reduced AGE-induced ROS generation. The incubation of HUVEC with 100 μg/mL of AGEs caused a considerable increase in THP-1 monocytic cell adhesion, but this adhesion was reduced by the treatment of TCE. These results suggest that TCE is a potential agent for alleviating diabetic complications.     

Amelioration of compound 4,4′-diphenylmethane-bis(methyl)carbamate on high mobility group box1-mediated inflammation and oxidant stress responses in human umbilical vein endothelial cells via RAGE/ERK1/2/NF-κB pathway

High mobility group box-1 (HMGB1), a secreted nuclear protein, acts as an inflammatory mediator and has been implicated in pathophysiological damage of diabetic vascular complications. A compound 4,4′-diphenylmethane-bis(methyl) carbamate (CM1) has a protective activity on advanced glycation end products (AGEs)-induced endothelial dysfunction in our previous study. The aim of this study was to investigate whether CM1 could attenuate HMGB1-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs), and also elucidate the possible underlying mechanism. The pre-treatment of CM1 (10^? 9 M) could inhibit significantly the migration of macrophages in co-incubation with HUVECs system. HMGB1 stimulated intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta1 (TGF-β1) and receptor for advanced glycation end products (RAGE) protein expression in HUVECs, which were inhibited by pretreatment with CM1. Furthermore, it also reduced significantly reactive oxygen species (ROS) generation and inflammatory cytokine interleukin-6 (IL-6) level in co-incubation system. Immunofluorescence and Western blotting assays showed that CM1 could attenuate HMGB1-induced intracellular ERK1/2 and NF-kB activation in HUVECs. Our findings indicated that CM1 attenuated HMGB1-mediated endothelial activation by ameliorating inflammation and oxidant stress responses via RAGE/ERK1/2/NF-κB pathway.     

α-硫辛酸对AGEs作用下血管内皮细胞PD-L1表达的影响

目的探讨α-硫辛酸(LA)对糖基化终产物(AGEs)作用下的人脐静脉血管内皮细胞株(HUVEC)表面程序性死亡配体1(PD-L1)分子表达及培养上清液中可溶性PD-L1(sPD-L1)浓度的影响。方法实验分四组:正常对照组(C组:RPMI1640培养);糖基化牛血清白蛋白(AGE-BSA)组[培养液分别为AGE-BSA50mg/ml(AG50组)、200mg/ml(AG200组)和400mg/ml(AG400组)];牛血清白蛋白(BSA)对照组[培养液分别为BSA50mg/ml(BG50组)、200mg/ml(BG200组)和400mg/ml(BG400组)];药物干预组[培养液分别为RPMI1640+200μmol/LLA(C+LA200组)、200mg/mlAGE-BSA+200μmol/LLA(AG200+LA200组)]。孵育72h后,检测各组HUVEC细胞表面PD-L1的表达及上清液中sPD-L1浓度的变化。结果不同浓度AGE-BSA作用细胞72h,PD-L1的表达及sPD-L1浓度较对照组显著升高(P<0.01),其效应呈现一定的浓度依赖性。在LA干预下,AG200+LA200组PD-L1表达及s...     

Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication

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. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.     

糖基化终末产物调节氧化应激影响脐血间充质干细胞增殖及普罗布考保护作用

目的探讨糖基化终末产物(AGEs)对人脐血来源的间充质干细胞(MSCs)增殖的影响及普罗布考的保护作用。方法体外分离培养脐血MSCs,应用流式细胞术对细胞表面抗原CD34、CD45、CD105进行表型鉴定。将MSCs分为白蛋白(BSA)对照组、糖基化修饰的牛血清白蛋白(AGE-BSA)浓度效应组和普罗布考干预组。应用WST法检测各组细胞增殖情况。应用二氯醋酸荧光素探针和氧化应激检测试剂盒检测各组细胞活性氧(ROS)、超氧化物岐化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)含量。结果流式细胞鉴定显示,脐血MSCs不表达CD34、CD45,表达CD105。与对照组相比,AGE-BSA组增殖能力下降,ROS含量增加,SOD和GSH-Px活性下降。与AGE-BSA组相比,普罗布考在10、20、50、100μmol/L范围内促进细胞增殖,降低细胞ROS含量,增加SOD和GSH-Px活性。结论 AGEs能够调节氧化应激,抑制脐血MSCs增殖。普罗布考的作用机制可能是通过抑制ROS生成和提高抗氧化酶活性来保护脐血MSCs增殖能力。     

Novel therapeutics for diabetic micro- and macrovascular complications

Diabetic patients have a two- to four-fold increased risk for the development of microvascular (renal, neuronal and retinal) and macrovascular complications. Unfortunately, these complications may develop in both Type 1 and Type 2 diabetic patients even with careful glycaemic, blood pressure and lipid control. With the worldwide increase in the incidence diabetes, new strategies to prevent the complications are urgently needed. Mediators of vascular damage of diabetes include poor glycemic control, lipoprotein abnormalities, hypertension, oxidative stress, inflammation and advanced glycation end-products (AGEs), which are modified proteins formed by non-enzymatic glycation. AGEs are resistant to enzymatic degradation and therefore very stable, thus their accumulation continues throughout aging. AGE accumulation causes arterial stiffening in the vessel wall, glomerulosclerosis in the kidney, and vascular hyperpermeability in the retina. Through their interaction with their putative receptor the so-called receptor for AGEs (RAGE), AGEs activate endothelial cells and macrophages, generate reactive oxygen species (ROS), induce overexpression of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1), and quench nitric oxide (NO). The pharmacological treatment currently available for either Type 1 or Type 2 diabetic patients does not directly address the excess accumulation of AGEs. Novel compounds that inhibit AGE formation, cleave AGE cross-links or reverse their interaction with RAGE are now accessible and could prove useful in meeting this challenge. Other strategies such as inhibition of the hexosamine pathway, vitamin therapy to reduce oxidation and AGE accumulation, reduction of the ROS, or blocking the actions of growth factors or intracellular messengers of cell differentiation are also currently under research. This review will recount recent advances in the development of therapeutic approaches for inhibiting and treating the development of diabetic end-organ damage.     

Advanced glycation end products (AGEs) activate mast cells

BACKGROUND AND PURPOSE

Advanced glycation endproducts (AGEs) represent one of the many types of chemical modifications that occur with age in long-lived proteins. AGEs also accumulate in pathologies such as diabetes, cardiovascular diseases, neurodegeneration and cancer. Mast cells are major effectors of acute inflammatory responses that also contribute to the progression of chronic diseases. Here we investigated interactions between AGEs and mast cells.

EXPERIMENTAL APPROACHES

Histamine secretion from AGEs-stimulated mast cells was measured. Involvement of a receptor for AGEs, RAGE, was assessed by PCR, immunostaining and use of inhibitors of RAGE. Production of reactive oxygen species (ROS) and cytokines was measured.

KEY RESULTS

Advanced glycation endproducts dose-dependently induced mast cell exocytosis with maximal effects being obtained within 20 s. RAGE mRNA was detected and intact cells were immunostained by a specific anti-RAGE monoclonal antibody. AGEs-induced exocytosis was inhibited by an anti-RAGE antibody and by low molecular weight heparin, a known RAGE antagonist. RAGE expression levels were unaltered after 3 h treatment with AGEs. AGE-RAGE signalling in mast cells involves Pertussis toxin-sensitive G_i-proteins and intracellular Ca²⁺ increases as pretreatment with Pertussis toxin, caffeine, 2-APB and BAPTA-AM inhibited AGE-induced exocytosis. AGEs also rapidly stimulated ROS production. After 6 h treatment with AGEs, the pattern of cytokine secretion was unaltered compared with controls.

CONCLUSIONS AND IMPLICATIONS

Advanced glycation endproducts activated mast cells and may contribute to a vicious cycle involving generation of ROS, increased formation of AGEs, activation of RAGE and to the increased low-grade inflammation typical of chronic diseases.     

Regulation of advanced glycation end product (AGE)-receptor (RAGE) system by PPAR-gamma agonists and its implication in cardiovascular disease

Non-enzymatic modification of proteins by reducing sugars leads to the formation of advanced glycation end products (AGEs), whose process has been reported to progress under physiological aging, oxidative stress or diabetic conditions. There is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of cardiovascular disease (CVD). Indeed, engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory and thrombogenic responses in various types of cells, including endothelial cells, smooth muscle cells, macrophages and renal cells, thus playing an important role in the development and progression of vascular injury in both diabetes and non-diabetes. These observations suggest that the inhibition of AGE formation, down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising therapeutic target for preventing CVD. Recently, peroxisome proliferator-activated receptor-γ (PPARγ) is involved in not only adipocyte differentiation, but also vascular homeostasis. Therefore, in this study, we review effects of PPARγ agonists on the AGE–RAGE system and their implication in CVD.     

Effect of PKC-β Signaling Pathway on Expression of MCP-1 and VCAM-1 in Different Cell Models in Response to Advanced Glycation End Products (AGEs)

Advanced glycation end products (AGEs) are compounds classified as uremic toxins in patients with chronic kidney disease that have several pro-inflammatory effects and are implicated in the development of cardiovascular diseases. To explore the mechanisms of AGEs–endothelium interactions through the receptor for AGEs (RAGE) in the PKC-β pathway, we evaluated the production of MCP-1 and VCAM-1 in human endothelial cells (HUVECs), monocytes, and a coculture of both. AGEs were prepared by albumin glycation and characterized by absorbance and electrophoresis. The effect of AGEs on cell viability was assessed with an MTT assay. The cells were also treated with AGEs with and without a PKC-β inhibitor. MCP-1 and VCAM-1 in the cell supernatants were estimated by ELISA, and RAGE was evaluated by immunocytochemistry. AGEs exposure did not affect cell viability, but AGEs induced RAGE, MCP-1, and VCAM-1 expression in HUVECs. When HUVECs or monocytes were incubated with AGEs and a PKC-β inhibitor, MCP-1 and VCAM-1 expression significantly decreased. However, in the coculture, exposure to AGEs and a PKC-β inhibitor produced no significant effect. This study demonstrates, in vitro, the regulatory mechanisms involved in MCP-1 production in three cellular models and VCAM-1 production in HUVECs, and thus mimics the endothelial dysfunction caused by AGEs in early atherosclerosis. Such mechanisms could serve as therapeutic targets to reduce the harmful effects of AGEs in patients with chronic kidney disease.     

葛根素对糖尿病大鼠主动脉糖基化终产物的形成及其受体表达的影响

目的　观察葛根素 (Puerarin ,Pue)对糖尿病 (DM)大鼠主动脉糖基化终产物 (AGEs)的形成及其受体 (RAGEmRNA)表达的影响。方法　以STZ诱导DM大鼠模型 ,并将DM大鼠随机分为DM对照组 (DM)、不同剂量葛根素治疗组 (0 5、0 2 5、0 1 2 5g·kg-1 ,ig )和氨基胍治疗组 (0 1g·kg-1 ,ig) ,另设一正常对照组 ,给药 1 2wk后 ,分别以葡萄糖氧化酶法测定血糖 ,NBT法测定血清果糖胺的含量 ,采用荧光法、RT PCR方法分别对主动脉AGEs的沉积及RAGEmRNA的表达进行检测。结果　Pue治疗后DM大鼠血糖、血清果糖胺含量明显降低 ,主动脉AGEs的形成量也明显低于DM模型组 (P <0 0 1 ) ,其治疗作用与氨基胍 (AG)相当 ;RAGE主要在内皮细胞表达 ,其表达量与AGEs的沉积量呈明显正相关 ,而葛根素也可明显下调RAGEmRNA在DM大鼠主动脉中的表达 (P<0 0 1 )。结论　葛根素可通过有效降低糖尿病大鼠血糖、血清果糖胺的含量 ,减少主动脉AGEs的沉积 ,下调主动脉中RAGEmRNA的表达 ,即通过抑制糖尿病大鼠主动脉非酶糖化的形成来防治DM血管病变的发生发展     

Crocetin prevents AGEs-induced vascular endothelial cell apoptosis.

Advanced glycation end products (AGEs) are causally correlated with diabetic vascular complications. AGEs triggered oxidative reaction then accelerated endothelial cell apoptosis is a critical event in the process of vascular complications. Crocetin, a carotenoid has been previously shown to have strong antioxidant activates. Therefore, this study was designed to investigate the role of crocetin on the prevention of AGEs-mediated cell apoptosis in bovine aortic endothelial cells (BEC) and the mechanisms involved. Exposure of BEC to 200 microg/ml AGEs for 48 h results in a significant increase in apoptotic rate, compared with control. AGEs-induced DNA fragmentation preferentially occurred in the S phase cells. Crocetin prevented AGEs-induced BEC apoptosis, which correlates with crocetin attenuation of AGEs mediated increase of intracellular reactive oxygen species (ROS) formation and elevation of intracellular Ca2+ concentration ([Ca2+]i) level (P<0.01 versus AGEs group). These results demonstrate that crocetin prevents AGEs-induced BEC apoptosis through ROS inhibition and [Ca2+]i stabilization and suggest that crocetin may exert a beneficial effect in preventing diabetes-associated vascular complications.     

Kinetics, role and therapeutic implications of endogenous soluble form of receptor for advanced glycation end products (sRAGE) in diabetes

Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) axis is implicated in the pathogenesis of diabetic vascular complications. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. Moreover, administration of a recombinant soluble form of RAGE (sRAGE), has been shown to suppress the development of accelerated atherosclerosis in diabetic apolipoprotein E-null mice. These observations suggest that exogenously administered sRAGE may capture and eliminate circulating AGEs, thus protecting against the AGEs-elicited tissue damage by acting as a decoy receptor. Recently, endogenous sRAGE has been identified in humans. However, there is few comprehensive review about the regulation and role of endogenous sRAGE in diabetes. In the former part of this paper, we review the role of the AGE-RAGE system in the pathogenesis of diabetic vascular complications. Then we summarize in the latter part of this review the kinetics and pathophysiological role of endogenous sRAGE in diabetes. We also discuss the possibility that endogenous sRAGE may be a therapeutic target for the prevention of diabetic vascular complications.