RAGE基因表达与糖尿病血管病变

晚期糖基化终末产物(AGEs)受体(RAGE)与其配体AGEs形成的AGEs—RAGE系统在糖尿病血管病变的发生、发展过程中起着重要作用。年龄及AGEs等多种因素均能调节RAGE基因的表达。糖尿病患者体内RAGE高表达加速了病人血管病变的发展过程，增加了病变的复杂性。阻断RAGE通路可缓解糖尿病血管病变。因此，RAGE可以作为治疗糖尿病血管病变的药物靶点，并为临床医师治疗糖尿病血管病变提供新思路。     

晚期糖基化终末产物:糖尿病肾病治疗的新靶点

晚期糖基化终末产物(AGEs)在体内的增加、蓄积会引起各种细胞功能障碍,促进糖尿病微血管并发症特别是糖尿病肾病的发生和发展.AGEs可引起肾脏功能障碍和结构改变.针对AGEs的药物如抑制AGEs形成的药物、AGEs交联裂解剂、阻断AGEs及其受体相互作用的药物、抑制AGEs受体的表达及其下游路径的药物,分别作用于不同的信号通路环节,但都具有减少AGEs对靶器官损伤的作用,对糖尿病肾病具有一定的治疗作用.     

糖基化终末产物与糖尿病慢性并发症

AGEs是指糖的醛基与蛋白质的氨基端在非酶催化的化学反应下生成的一类物质。人们最初认为AGEs只是蛋白质老化的标志，以便体内识别降解、清除老化的蛋白质。近年来，随着对糖尿病慢性病发症发病机制及病理改变的深入研究，对AGEs有了更全面的认识。人们最初认为AGEs只是蛋白质老化的标志。现在越来越多的事实表明，AGEs不仅与被修饰的大分子的降解有关．AGEs与其受体相互作用。能够激活多个信号传导通路，促进多种细胞因子的合成与释放。促使糖尿病并发症的发生发展。     

高级糖化终产物(AGEs)形成及其致病机理

高级糖化终产物（advanced glycation end-products：AGEs）是一组复杂且具有异质性的物质，它可引起细胞间分子的连接，造成细胞外基质蛋白不可逆的异常改变，AGEs修饰的蛋白通过与AGEs特异受体结合刺激机体产生细胞因子和氧自由基。AGEs同时也修饰细胞内蛋白，造成蛋白功能异常，终致结缔组织、晶状体、血管和神经等的病变。目前，AGE被认为参与糖尿病并发症、老化过程及动脉粥样硬化的发生发展。AGE浓度在人体血液中随着年龄、糖尿病病程及是否有并发症而变化。治疗AGE在体内的积累现已有一些药物，其中氨基胍正在进行Ⅲ期临床试验。     

RAGE基因表达与糖尿病血管病变

晚期糖基化终末产物(AGEs)受体(RAGE)与其配体AGEs形成的AGEsRAGE系统在糖尿病血管病变的发生、发展过程中起着重要作用。年龄及AGEs等多种因素均能调节RAGE基因的表达。糖尿病患者体内RAGE高表达加速了病人血管病变的发展过程,增加了病变的复杂性。阻断RAGE通路可缓解糖尿病血管病变。因此,RAGE可以作为治疗糖尿病血管病变的药物靶点,并为临床医师治疗糖尿病血管病变提供新思路。     

晚期糖基化终产物在糖尿病血管并发症中的作用机制

晚期糖基化终产物（AGEs）是蛋白质或脂质经过糖基化反应的产物。AGEs存在于糖尿病患者的血管中,促进动脉粥样硬化的发展。多种不同的细胞上AGEs的存在和聚集影响着细胞内外的结构和功能。AGEs通过与细胞外基质基底膜上的分子形成交联和与其受体（RAGE）结合引起多种微血管和大血管并发症。RAGE被AGEs激活后导致转录因子NF-κB和它的靶因子的表达。AGEs可诱发糜蛋白酶的表达和糜蛋白酶依赖性血管紧张素Ⅱ的生成,从而作用于糖尿病血管并发症的发展。     

糖基化终末产物在心血管病变中的作用机制

晚期糖基化终末产物（Advanced glycation end products, AGEs）是一组随着衰老、糖尿病以及肾功能衰竭逐渐积累于循环组织中的性质各异的分子。AGEs形成于还原糖的羰基和靶蛋白活性氨基的聚合，这种毒性分子与特异性受体相互作用可诱导体内多种病理过程。越来越多的证据表明AGEs参与了心血管病的发病过程。弄清AGEs在心血管疾病中的作用机制并在此基础上进行有效的干预，将对心血管疾病的防治起到重要作用。     

糖化和脂氧化终末产物与羰基应激

机体代谢紊乱引起氧化应激，导致反应性羰基化合物（RCO）大量增生，引起羰基应激。羰基应激促进体内糖基化终末产物（AGEs)和脂氧化终末产物（ALEs)的大量生成和蓄积。RCO可直接对细胞产生病理影响，也可通过促进AGEs或ALEs的蓄积而引起一系列病理损害。故采用抗氧化剂、羰基抑制和血液净化治疗可抑制AGEs和ALEs的生成，为糖尿病及其并发症的治疗提供了思路。     

糖尿病足溃疡局部炎性反应状态与伤口愈合的关系

糖尿病伤口局部的炎性反应状态表现为炎性反应起始晚、持续时间长、消退障碍,与巨噬细胞对凋亡中性粒细胞的吞噬减少和促炎消退脂类介质分泌减少有关.而炎性反应过程中中性粒细胞数量和功能的异常、不同表型巨噬细胞比例异常、促炎/抗炎因子失平衡、晚期糖基化终末产物(AGEs)/细胞外新发现的AGEs受体结合蛋白(EN-RAGEs)和AGEs受体相互作用干扰了参与伤口愈合的多种细胞和细胞外基质的功能,导致糖尿病伤口愈合障碍.     

糖基化终末产物与糖尿病慢性并发症

AGEs是指糖的醛基与蛋白质的氨基端在非酶催化的化学反应下生成的一类物质.人们最初认为AGEs只是蛋白质老化的标志,以便体内识别降解、清除老化的蛋白质[1].近年来,随着对糖尿病慢性病发症发病机制及病理改变的深入研究,对AGEs有了更全面的认识.人们最初认为AGEs只是蛋白质老化的标志[1].现在越来越多的事实表明,AGEs不仅与被修饰的大分子的降解有关,AGEs与其受体相互作用,能够激活多个信号传导通路,促进多种细胞因子的合成与释放,促使糖尿病并发症的发生发展.     

糖尿病大鼠主动脉糖化终产物的免疫组化研究

目的　研究糖尿病时主动脉壁非酶糖化的程度以及非酶糖化机制在糖尿病血管重建和慢性并发症发生发展中的作用。方法　应用抗糖化终产物（ＡＧＥｓ） 多克隆抗体,对糖尿病大鼠和氨基胍治疗后的糖尿病大鼠进行主动脉壁ＡＧＥｓ 的免疫组化研究,计算机图像处理系统定量分析。结果糖尿病时主动脉壁中膜ＡＧＥｓ 的相对面积呈进行性增加,４ 周时其相对面积就显著大于对照组（ Ｐ＜０．０１）,氨基胍治疗４ 周后主动脉壁中膜ＡＧＥｓ 的相对面积较糖尿病组显著降低（ Ｐ＜ ０．０５）,治疗２４周后降低更为明显（Ｐ＜ ０．０１）。结论　主动脉壁ＡＧＥｓ 的免疫组化定量研究能更直观地反映血管组织非酶糖化的程度,非酶糖化是引起血管重建的重要机制之一。     

Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory

Epidemiological studies have suggested that cumulative diabetic exposure, namely prolonged exposure to chronic hyperglycemia, contributes to the increased risk of cardiovascular disease (CVD) in diabetes. The formation and accumulation of advanced glycation end‐products (AGEs) have been known to progress under hyperglycemic conditions. Because AGEs‐modified collagens are hardly degraded and remain in diabetic vessels, kidneys and the heart for a long time, even after glycemic control has been achieved, AGEs could become a marker reflecting cumulative diabetic exposure. Furthermore, there is a growing body of evidence that an interaction between AGEs and the receptor for AGEs (RAGE) plays a role in the pathogenesis of CVD. In addition, AGEs induce the expression of RAGE, thus leading to sustained activation of the AGEs–RAGE axis in diabetes. Herein we review the pathological role of the AGEs–RAGE axis in CVD, focusing particularly on the phenomenon of metabolic memory, and discuss the potential clinical usefulness of measuring circulating and tissue levels of AGEs accumulation to evaluate diabetic macrovascular complications.     

晚期糖基化终产物单克隆抗体的特异性和抗原表位鉴定

目的探讨晚期糖基化终产物在糖尿病慢性并发症发生发展过程中的作用,对我们制备的5株抗糖基化终产物单克隆抗体进行特异性及抗原表位鉴定。方法采用间接酶联免疫吸附法和蛋白印迹术分析所制备单克隆抗体与对照物(人血清白蛋白、孵育人血清白蛋白、牛血清白蛋白)的交叉反应性及其针对的抗原表位。用所得单克隆抗体对正常对照、糖尿病及透析病人血清和糖尿病大鼠主动脉进行糖基化终产物的蛋白印迹分析。结果所得抗体与糖基化终产物特异性结合,而与对照物结合较低,提示它们与糖基化终产物结合能力和特异性较强。初步鉴别其抗原表位非羧甲基赖氨酸。在正常对照、糖尿病及透析病人血清中检测到葡萄糖源性糖基化终产物。用所得单克隆抗体行蛋白印迹分析,发现糖尿病高血压大鼠主动脉含糖基化终产物特异显色,而正常对照组不明显。结论5株抗糖基化终产物单克隆抗体细胞株具较高抗原特异性,可定性发现血清和组织中的糖基化终产物。     

高糖代谢记忆与糖尿病并发症

高糖"代谢记忆"是影响糖尿病并发症的重要因素,早期血糖控制情况可对并发症产生持久影响.氧化应激和晚期槠基化终末产物(AGEs)是形成高糖"代谢记忆"的基础,同时也是高糖"代谢记忆"参与糖尿病并发症的主要途径.在氧化应激途径中,活性氧簇(ROS)激活与糖尿病并发症相关;在AGEs途径中,AGEs引发的后续效应介导并发症的发生.减弱氧化应激和AGEs的作用,清除有害的代谢记忆,有望成为延缓糖尿病慢性并发症的治疗措施.     

The meaning of serum levels of advanced glycosylation end products in diabetic nephropathy

It has been reported that advanced glycosylation end products (AGEs) play an important role in the development of diabetic complications. To evaluate the relationship between serum AGEs and diabetic nephropathy, we measured serum AGE levels in diabetic patients with normoalbuminuria (N), microalbuminuria (M), overt proteinuria (O), and hemodialysis (HD), non diabetic patients with nephropathy, and age-matched control subjects using the enzyme-linked immunosorbent assay (ELISA). Urine AGE levels were also measured in these subjects except group HD. Serum AGE levels in diabetic patients were not significantly higher than those in the normal subjects. When we compared serum AGE levels among various stages of diabetic nephropathy, groups O and HD had significantly higher serum AGE levels than the other groups. Serum AGE levels in group HD were almost 6-fold higher than those in groups N and M. In contrast, there were no significant differences in urinary AGE levels among any diabetic groups. As for the variables that determine serum AGE levels in diabetic patients, there was no significant correlation between serum AGEs and fasting blood glucose, hemoglobin A1c (HbA1c), or duration of diabetes. In contrast, serum AGEs showed a strong correlation with serum creatinine and an inverse correlation with creatinine clearance. To evaluate the relationship between serum AGEs and oxidative stress in diabetic nephropathy, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde (MDA), which are biological markers of total oxidative stress in vivo, were also examined. Both urinary 8-OHdG and serum MDA levels were significantly higher in diabetic patients with proteinuria versus those without proteinuria. However, there was no significant correlation between serum AGEs and urinary 8-OHdG or serum MDA levels in diabetic patients. These results suggest that the accumulation of serum AGEs in diabetic nephropathy may be mainly due to decreased removal in the kidney rather than increased production by high glucose levels or oxidative stress.     

Advanced glycation end-products: Implications for diabetic and non-diabetic nephropathies

Glycation is the process whereby sugars bind to the free amine residues of proteins. These newly formed modified molecular species are known as ‘advanced glycation end-products’, or AGEs. AGE toxicity may occur through at least three mechanisms: interaction with the receptor for AGEs (RAGE); tissue deposition; and in situ glycation. AGEs trigger proinflammatory, profibrotic and procoagulant cellular responses that are capable of damaging tissues, often targeting particular organs. In diabetic patients, the conditions needed to promote AGE formation are all present, and are further accentuated by accompanying renal failure. The aim of this review is to outline the involvement of AGEs in the various forms of renal pathology associated with diabetic and non-diabetic nephropathies. AGEs are present in all renal compartments in diabetic patients, including the vessels, glomeruli, tubules and interstitium. Many cell types may be activated—specifically, endothelial, tubular and mesangial cells, and podocytes. AGEs play a major role in the accumulation of extracellular matrix, as occurs in diabetic glomerulosclerosis, and are also involved in most diabetic (renovascular, microangiopathic and glomerular) and non-diabetic renal injury associated with progressive glomerulosclerosis and ageing.     

Glycotoxins in the diet promote diabetes and diabetic complications

Oxidant stress underlies diabetes and diabetic complications, including cardiovascular, renal, and retinal disease. Advanced glycation end products (AGEs), or glycotoxins, are a significant contributor to oxidant stress in diabetes. The diet is a major, unrecognized source of AGEs. Importantly, reduction of dietary AGEs decreases circulating inflammatory markers in both diabetic patients and prediabetic patients and complications in animal models. This beneficial outcome requires only a 50% decrease in dietary AGEs, making this necessary intervention practical and inexpensive.     

Hepatocyte growth factor has a role in the amelioration of diabetic vascular complications via autophagic clearance of advanced glycation end products: Dispo85E, an HGF inducer, as a potential botanical drug

The aim of this study was to evaluate the effect and elucidate the potential mechanism of the extract of rhizomes from Dioscorea alata L. cv. Phyto, Dispo85E, on accelerating the elimination of advanced glycation end products (AGEs) in vitro and in vivo. Primary mouse nonparenchymal cells (NPCs) were used to evaluate the drug effect on AGEs clearance and autophagic-lysosomal activity. In an animal study, we used AGEs-induced diabetic mice to evaluate the drug effect on AGEs-induced vascular complications. Our results indicated that Dispo85E enhanced the endocytosis and degradation activity of AGEs in hepatic NPCs. Furthermore, the hepatocyte growth factor (HGF) expression level was positively correlated with the clearance capacity of the AGEs in NPCs after Dispo85E treatment. In addition, the effects of Dispo85E on the degradation and uptake capability of ¹⁴C-AGEs were abolished in the presence of an anti-HGF neutralizing antibody. We further demonstrated that recombinant mouse HGF could enhance the endocytosis and autophagic clearance of AGEs in NPCs. The in vivo data indicated that Dispo85E increased hepatic HGF messenger RNA expression levels and decreased serum AGEs level in diabetic mice. Moreover, the function of retina and kidneys was improved by Dispo85E treatment in AGEs-induced diabetic mice. These results suggest that HGF may have an important role in the elimination of AGEs. This study suggests that Dispo85E is a botanical drug with a novel mechanism that enhances the clearance of AGEs through HGF-induced autophagic-lysosomal pathway and is a candidate drug for the treatment of diabetic vascular complications.     

Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes

We have recently found that soluble form of receptor for advanced glycation end products (sRAGE) levels are positively associated with inflammatory biomarkers and the presence of coronary artery disease (CAD) in type 2 diabetic patients. Since advanced glycation end products (AGEs) up-regulate RAGE expression and endogenous sRAGE could be generated from the cleavage of cell surface RAGE, it is conceivable that sRAGE is positively associated with circulating AGEs levels in diabetes. In this study, we examined whether sRAGE were correlated to circulating levels of AGEs and soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes. Eighty-two Japanese type 2 diabetic patients underwent a complete history and physical examination, determination of blood chemistries, sRAGE, AGEs, sVCAM-1 and sICAM-1. Multiple regression analysis revealed that serum levels of AGEs and sVCAM-1 were independently correlated with sRAGE. This study demonstrated that serum levels of sRAGE were positively associated with circulating AGEs and sVCAM-1 levels in type 2 diabetic patients. Our present observations suggest sRAGE level may be elevated in response to circulating AGEs, thus being a novel marker of vascular injury in patients with type 2 diabetes.     

橙皮苷对STZ糖尿病大鼠肾脏功能和形态的影响

观察橙皮苷对链脲佐菌素导致的糖尿病大鼠肾脏功能和形态的影响,并与氨基胍进行比较。结果表明:（1）两治疗组大鼠尿蛋白排泄量显著低于对照组P<0.05）;（2）两治疗组肾组织AGEs和LPO含量显著低于对照组（P<0.01,P<0.05）:（3）治疗组肾小球系膜增生和基底膜增厚明显减轻。提示橙皮苷在抑制蛋白非酶糖基化、预防糖尿病肾脏并发症方面具有与氨基胍相似的作用。