Controlling the receptor for advanced glycation end‐products to conquer diabetic vascular complications

Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long‐term diabetes. Extensive intracellular and extracellular formation of advanced glycation end‐products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor‐dependent mechanisms are involved in AGE‐induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE‐binding receptor, is now recognized as a member of pattern‐recognition receptors and a pro‐inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00191.x, 2012)     

Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes

Aims/hypothesis Activation of the receptor for advanced glycation end products (RAGE, also known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs and the severity of nephropathy in type 2 diabetic patients.Materials and methods We recruited 150 healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-RNase.Results Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1–1,423.0] interquartile range vs 1,002.6 [726.5–1,345.3], p<0.05) and AGEs (4.07±1.13, SD, unit/ml vs 3.39±1.05, p<0.01) than controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between the severity of nephropathy and sRAGE (p=0.01). In diabetic subjects, serum log(sRAGE) correlated with AGEs (r=0.27, p<0.001), log(plasma creatinine) (r=0.31, p<0.001), log(urine AER) (r=0.24, p<0.01) and log(triglycerides) (r=0.15, p<0.01). On stepwise linear regression analysis, AGEs and creatinine levels were the main independent determinants of sRAGE concentration.Conclusions/interpretation Serum sRAGE levels and circulating AGEs are associated with the severity of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether endogenous sRAGE potentially influences the development of diabetic vascular complications.     

晚期糖基化终末产物受体在急性肺损伤中作用的研究进展

晚期糖基化终末产物受体是细胞表面模式识别受体,在Ⅰ型肺泡上皮细胞有丰富表达.近年研究表明急性肺损伤时,支气管肺泡灌洗液及血浆中晚期糖基化终末产物受体含量明显升高,且与肺损伤程度密切相关.另一方面,它与相应配体结合激活细胞内信号通路,参与急性肺损伤的炎症激活和放大过程.晚期糖基化终末产物受体将在判断急性肺损伤患者病情、预...     

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients

BACKGROUND:

Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress – all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis.

OBJECTIVES:

To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI.

METHODS:

Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients.

RESULTS:

sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients.

CONCLUSIONS:

Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.     

晚期糖基化终末产物受体在心血管疾病中的研究进展

晚期糖基化终末产物受体(RAGE)属于细胞表面免疫球蛋白超家族中的一员,广泛表达于人体内皮细胞、平滑肌细胞、系膜细胞、心肌细胞、单核巨噬细胞和神经元细胞等。RAGE不仅参与炎症反应,还与糖尿病慢性并发症的发生、发展,类风湿性关节炎,肿瘤的侵袭和转移,阿尔茨海默病,慢性肾病等有关。现主要论述其在心血管疾病中的作用。     

Blockade of the receptor for advanced glycation end products attenuates acetaminophen-induced hepatotoxicity in mice

BACKGROUND AND AIM: Severe injury to the liver, such as that induced by toxic doses of acetaminophen, triggers a cascade of events leading to hepatocyte death. It is hypothesized that activation of the receptor for advanced glycation end products (RAGE) might contribute to acetaminophen-induced liver toxicity by virtue of its ability to generate reactive oxygen species, at least in part via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and thereby activate downstream signaling pathways leading to cellular injury. METHODS: A model was employed in which toxic doses of acetaminophen (1125 mg/kg) were administered to C57BL/6 mice. To block RAGE, mice received murine soluble (s) RAGE, the extracellular ligand binding domain of the receptor that acts as a decoy to interrupt ligand-RAGE signaling. RESULTS: Animals treated with sRAGE displayed increased survival compared with vehicle treatment, and markedly decreased hepatic necrosis. Consistent with an important role for RAGE-triggered oxidant stress in acetaminophen-induced injury, a significant reduction of nitrotyrosine protein adducts was observed in hepatic tissue in sRAGE-treated versus vehicle-treated mice receiving acetaminophen, in parallel with significantly increased levels of glutathione. In addition, pro-regenerative cytokines tumor necrosis factor-alpha and interleukin-6 were increased in sRAGE-treated versus vehicle-treated mice. CONCLUSION: These findings implicate RAGE-dependent mechanisms in acetaminophen-induced liver damage and suggest that blockade of this pathway may impart beneficial effects in toxin-induced liver injury.     

Correlation between soluble receptor for advanced glycation end products levels and coronary artery disease in postmenopausal nondiabetic women

BACKGROUNDThe established cardiovascular risk factors cannot explain the overall risk of coronary artery disease (CAD), especially in women. Therefore, there is a growing need for the assessment of novel biomarkers to identify women at risk. The receptor for advanced glycation end products (RAGE) and its interaction with the advanced glycation end product (AGE) ligand have been associated with atherogenesis. The soluble fraction of RAGE (sRAGE) antagonizes RAGE signaling and exerts an antiatherogenic effect.AIMThe study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODSThis case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups. Group I included 55 angiographically proven CAD subjects with > 50% stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had < 50% stenosis of the coronary arteries. Stenosis was confirmed by invasive angiography. Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTSWe observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls (P < 0.05). Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD (P = 0.01). Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL (lowest quartile) had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSIONOur findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women. Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.     

Soluble receptor for advanced glycation end products (sRAGE) is present at high concentrations in the lungs of children and varies with age and the pattern of lung inflammation

Background and objective: The soluble receptor for advanced glycation end products (sRAGE) plays an important role in inflammation. Few studies have looked at sRAGE levels in human lungs, and there is no information in children. Therefore, this study aimed to compare bronchoalveolar lavage fluid (BALF) and plasma sRAGE concentrations in children in relation to age and inflammation. Methods: BAL was performed in 76 children, and BALF and plasma sRAGE levels were determined by enzyme‐linked immunosorbent assay. Results: sRAGE levels were fourfold higher in BALF than in plasma (P < 0.001). BALF sRAGE was inversely proportional to age (r = ?0.333, P = 0.008) and serum immunoglobulin A (r = ?0.283, P = 0.028). Plasma sRAGE showed a positive correlation to the percentage of BAL macrophages and negative correlation to the percentage of neutrophils and lymphocytes (P < 0.05). Multivariate linear regression analysis identified that the percentage of BAL lymphocytes and neutrophils were significant independent predictors of plasma sRAGE levels, while age and the percentage of BAL macrophages independently predicted BALF sRAGE levels. Conclusions: In children, sRAGE is present at higher concentrations in the lung compared with blood. It appears that sRAGE varies with age, and hence future studies of sRAGE in paediatric lung disease require age matching. The significant relationship between sRAGE and lung inflammation warrants further research.     

2型糖尿病对急性ST段抬高型心肌梗死患者血清可溶性晚期糖基化终产物受体水平的影响

目的 观察2型糖尿病(T2DM)伴急性ST段抬高型心肌梗死(STEMI)患者血清可溶性晚期糖基化终产物受体(sRAGE)水平的变化。方法 选择60例STEMI患者,其中伴T2DM者为Ⅰ组,无糖尿病者为Ⅱ组,每组30例;并选取30例T2DM无并发症者为Ⅲ组;选取30例健康体检者为Ⅳ组。均测定血清sRAGE及心肌肌钙蛋白(cTNI)水平。结果 sRAGE_Ⅰ组为(1149.0±188.6)ng/L,sRAGE_Ⅱ组为(926.6±165.4)ng/L,sRAGE_Ⅲ组为(509.4±78.9)ng/L,sRAGE_Ⅳ组为(696.8±101.8)ng/L,差异有统计学意义(P=0.000);sRAGE曲线下面积(AUC_sRAGE)为0.967±0.014(P=0.000,95%CI：0.940~0.994), AUC _cTNI为0.875(P=0.000,95%CI：0.807~0.944);sRAGE截断点取761.550 ng/L时,灵敏度(Se)为91.7%,特异度(Sp)为83.0%,约登指数(YI)为83.4%;cTNI截断点取0.060 μg/L时,Se为76.7%,Sp为98.3%,YI为75.0%。结论 急性ST段抬高型心肌梗死伴2型糖尿病患者血清sRAGE水平增高,sRAGE对急性ST段抬高型心肌梗死可能有早期诊断价值。     

Reduced endogenous secretory receptor for advanced glycation end products (esRAGE) in young people with Type 1 diabetes developing microalbuminuria

Aims The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA). Methods Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA?), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA? subjects in relation to the time of MA onset. Results Overall, esRAGE levels were significantly lower in MA+ than in MA? subjects (0.727 ± 0.396 vs. 0.936 ± 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 ± 0.410 vs. 0.956 ± 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 ± 0.433 vs. 0.948 ± 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA_1c) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12–0.98); P = 0.04), independently of HbA_1c. Conclusions In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication.     

Low plasma levels of the soluble receptor for advanced glycation end products in HIV-infected patients with subclinical carotid atherosclerosis receiving combined antiretroviral therapy

Objective

Combined antiretroviral therapy (cART) has significantly improved the survival rate and quality of life for HIV-infected subjects, but it contributes to the development of metabolic complications including coronary artery disease (CAD). Recent studies have reported that high plasma levels of the soluble receptor for advanced glycation end products (sRAGE) were associated with a lower incidence of CAD in non-HIV infected patients. However, there has been no report of an association of sRAGE and subclinical carotid atherosclerosis in HIV-infected patients receiving cART.

Methods

We examined the association of circulating sRAGE in HIV-infected patients with carotid intima–media thickness (IMT) and other metabolic variables. We prospectively enrolled 76 HIV-infected patients receiving cART for ≥6 months.

Results

sRAGE had a significantly negative correlation with body mass index (r = −0.324, p = 0.005), waist-to-hip ratio (r = −0.335, p = 0.003), systolic blood pressure (BP) (r = −0.359, p = 0.002), diastolic BP (r = −0.343, p = 0.004), total cholesterol (r = −0.240, p = 0.037), low-density lipoprotein-cholesterol (r = −0.284, p = 0.024), log(homeostasis model assessment of insulin resistance [HOMA-IR]) (r = −0.380, p = 0.002) and carotid IMT including max-IMT and mean-IMT (r = −0.358, p = 0.001 and r = −0.329, p = 0.004, respectively). By the use of multiple stepwise regression analyses, systolic BP (p = 0.001) and log[HOMA-IR] (p = 0.001) remained significant independently.

Conclusions

These results suggest that sRAGE may have a protective effect against subclinical atherosclerosis by preventing inflammatory responses mediated by the activation of cell surface RAGE in HIV-infected patients receiving cART.     

内源分泌型晚期糖基化终末产物受体与糖尿病周围神经病变的相关性

目的 探讨2型糖尿病患者周围神经病变(DPN)与内源分泌型晚期糖基化终末产物受体(esRAGE)的关系.方法 收集2008年6月至2009年3月于福建医科大学第二医院内分泌科住院的2型糖尿病患者61例及门诊体检的健康志愿者24名,根据有无合并糖尿病周围神经病变将糖尿病患者分2组,DPN组62例,无DPN组19例.采用酶联免疫吸附法(ELISA)测定血浆esRAGE水平.应用肌电诱发电位仪进行神经功能检查.测定受试者血压、体重指数、空腹血糖、糖化血红蛋白(HbA1c)、血脂.采用student t检验和非参数Mann-Whitney U检验分析两组问数据,利用Logistic回归分析糖尿病周围神经病变的相关因素.结果 正常对照组和2型糖尿病组患者血浆esRAGE水平无明显差别[(0.28±0.13)μg/L和(0.25±0.15)μg/L,P＞0.05],但在2型糖尿病患者中合并DPN组和无合并DPN组之间血浆esRAGE水平差别有显著性意义[(0.21±0.14)μg/L和(0.33±0.13)μg/L,P＜0.01],两组之间的年龄和糖化血红蛋白(HbA1c)也存在差别,Logistic回归分析提示年龄、HbA1c、血浆esRAGE水平与糖尿病周围神经病变相关,esRAGE是糖尿病周围神经病变保护因素(OR=0.001,P＜0.05).结论 2型糖尿病患者血浆esRAGE水平和正常人无明显差别.esRAGE是2型糖尿病周围神经病变的保护因素,而年龄和HbAlc是其危险因素.     

Calcitriol modulates receptor for advanced glycation end products (RAGE) in diabetic hearts

Background

Receptor for advanced glycation end products (RAGE) signaling pathway plays a vital role in diabetic cardiovascular complications. Calcitriol has been shown to exert various beneficial cardiovascular effects. The purpose of this study is to determine whether calcitriol can modulate RAGE expression, and study the potential mechanisms in diabetic hearts.

Methods

Streptozotocin (65 mg/kg, intraperitoneal injection once) induced diabetic rats were treated with or without subcutaneous injections of calcitriol at a dose of 150 ng/kg/day for 4 weeks. Western blot was used to evaluate protein expressions of myocardial RAGE, TNF-α, p65 subunit of NF-κB (p65), α subunit of inhibitor of κB (IκBα), subunits of NADPH oxidase (NOX4 and p22^phox), angiotensin II type 1 receptor (AT1R), TGF-β1, TGF-β receptor I, total and phosphorylated SMAD2/3 and ERK, matrix metalloproteinases 2 (MMP2), tissue inhibitors of metalloproteinases 2 (TIMP2) and procollagen I.

Results

As compared to control, diabetic rats had increased expressions of cardiac RAGE, TNF-α, p22^phox, AT1R, and TGF-β1, which were significantly attenuated in the diabetic rats treated with calcitriol. Calcitriol-treated diabetic hearts also had lesser expressions of p-SMAD2/3 and p-ERK signaling than those of diabetic hearts. Moreover, diabetic hearts had increased expressions of MMP2 and procollagen I and decreased TIMP2. However, calcitriol reverted the diabetic effects in procollagen I but not in MMP2 or TIMP2.

Conclusions

Calcitriol decreased diabetic effects on RAGE and fibrosis, which may be caused by its modulation on AT1R and the anti-inflammatory and antioxidative potentials. Therefore, calcitriol may attenuate diabetic cardiomyopathy.