sRAGE Concentrations Research Articles

Soluble receptor of advanced glycation end-products and endothelial dysfunction in COPD

Chronic obstructive pulmonary disease (COPD) is accompanied by an increased cardiovascular risk which is aggravated by the incidence of acute exacerbations (AE). Endothelial function, as well as the soluble receptor for advanced glycation end-products (sRAGE), both markers of cardiovascular risk, has been shown to be decreased in stable COPD. We aimed to investigate a possible link between sRAGE and endothelial function in AE of COPD. We hypothesize that circulating levels of sRAGE and endothelial function are impaired during AE and improve after clinical recovery, respectively. We enrolled patients admitted to hospital due to an AE of COPD without overt cardiovascular comorbidities. Study related procedures comprised spirometry, measurement of plasma sRAGE levels and the quantification of endothelial function by means of the flow-mediated dilation technique (FMD). All measurements were scheduled during hospitalization and after confirmed clinical stability. We recruited 29 patients (27% female) with moderate to severe COPD. Median sRAGE concentration was 525 pg/mL (371-770, 1st-3rd quartile) and mean FMD 6.7 ± 3.6% at AE. There was a significant increase of sRAGE levels to 876 pg/mL (633-1371, 1st-3rd quartile, p < 0.001) and a simultaneous improvement in FMD (10.0 ± 3.4%, p < 0.001) after clinical recovery. There was a significant positive association between sRAGE and FMD (regression coefficient = 2.43; p = 0.01) in our study sample. Our results indicate a substantial decrease in sRAGE levels and endothelial function during AE, with evidence of improvements after clinical recovery. sRAGE may contribute to cardiovascular risk in COPD.

Vitamin D Increases Serum Levels of the Soluble Receptor for Advanced Glycation End Products in Women With PCOS

Elevation of serum proinflammatory advanced glycation end products (AGEs) is involved in the pathogenesis of polycystic ovary syndrome (PCOS). The soluble receptor for AGEs (sRAGE) acts as a decoy by binding circulating AGEs. Vitamin D supplementation attenuates the deposition of AGEs in the vascular system of diabetic animals and improves some metabolic aspects of vitamin D-deficient women with PCOS. Additionally, serum anti-Mullerian hormone (AMH) is elevated in women with PCOS, reflecting abnormal ovarian folliculogenesis. The objective of the study was to evaluate the effect of 1,25 dihydroxyvitamin D3 (vit D3) supplementation on serum sRAGE and AMH in vitamin D-deficient women with PCOS. DESIGN, SETTINGS, PARTICIPANTS, AND INTERVENTION: Sixty-seven women with (n = 22) or without (control; n = 45) PCOS who were diagnosed with vitamin D deficiency were enrolled. Fifty-one women were replaced with oral vit D3 for 8 weeks (16 with PCOS and 35 controls) and 16 women were not treated (six with PCOS and 10 controls). Serum 25-hydroxyvitamin D (25 OH-D), sRAGE, and AMH concentrations were measured at baseline and after vit D3 supplementation in the treated group and 8 weeks apart in the nontreated group. Changes in serum sRAGE and AMH concentrations after vit D3 replacement were measured. In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r = -0.3, P = .01). In women with PCOS, but not in controls, vit D3 increased serum sRAGE (P = .03) and decreased serum AMH levels (P < .001). The increase in serum sRAGE positively correlated with the increase in serum 25 OH-D after supplementation in women with PCOS (r = 0.6, P = .01). In women with PCOS, vit D3 might exert a protective effect against the inflammatory action of AGEs by increasing circulating sRAGE. The normalization in serum AMH induced by vit D3 replacement suggests an improvement in folliculogenesis.

Total soluble and endogenous secretory receptor for advanced glycation endproducts (RAGE) in IBD

Background and aimsRecruitment and activation of neutrophils, with release of specific proteins such as S100 proteins, is a feature of inflammatory bowel disease (IBD). Soluble forms of the receptor for advanced glycation endproducts (sRAGE), and variants such as endogenous secretory (esRAGE), can act as decoy receptors by binding ligands, including S100A12. The aims of this study were to determine total sRAGE and esRAGE concentrations in patients with IBD and correlate these with C-reactive protein (CRP), endoscopic scores and clinical disease activity scores. MethodsEDTA-plasma was collected from patients undergoing colonoscopy including those with Crohn's disease (CD: n=125), ulcerative colitis (UC: n=79) and control patients without endoscopic signs of inflammation (non-IBD: n=156). Concentrations of sRAGE and esRAGE were determined by enzyme-linked immunosorbent assay and plasma CRP concentrations measured. Standard clinical disease activity and endoscopic severity scores were defined for all subjects. ResultsPlasma sRAGE concentrations were lower in UC (but not CD) than non-IBD subjects (p<0.01). Whilst sRAGE concentrations correlated negatively with endoscopic activity in UC (p<0.05), this was not seen in CD. In contrast, esRAGE correlated negatively with disease activity in both UC (p=0.002) and CD (p=0.0001). Furthermore, sRAGE and esRAGE concentrations correlated inversely with CRP values (p<0.0001). ConclusionsAlthough total sRAGE varied with activity in UC, esRAGE concentrations correlated inversely with endoscopic disease activity and CRP levels in both UC and CD. Additional studies are required to further define the significance of sRAGE and esRAGE in IBD.

Circulating levels of soluble receptor for advanced glycation end product are inversely associated with vascular calcification in patients on haemodialysis independent of S100A12 (EN‐RAGE) levels

The receptor for advanced glycation end products (RAGE) has emerged as a central regulator of vascular inflammation and atherosclerosis. Soluble RAGE (sRAGE) has an anti-inflammatory effect by quenching ligands for RAGE. On the other hand, extracellular RAGE-binding protein S100A12 (EN-RAGE) shows a pro-inflammatory effect in a way, but may play pleiotropic roles related to inflammatory process. Therefore, we determined the levels of sRAGE and S100A12 in haemodialysis (HD) patients and evaluated their relationship with vascular calcification. We performed a cross-sectional study with 199 HD patients. Plain X-ray images of the lateral lumbar spine from all subjects were studied to calculate semiquantitative vascular calcification scores (VCS), as described by Kauppila. Commercially available enzyme linked immunosorbent assay (ELISA) kits were used to quantify the serum concentration of sRAGE and S100A12. The patients were 57.1 ± 13.7 years of age; 54.3% were male, 49.2% were diabetic, and 36.2% had a history of cardiovascular disease. In a univariate analysis, serum sRAGE was negatively associated with VCS (log sRAGE, r=-0.208, P=0.003), whereas S100A12 showed a positive tendency (log S100A12, r=0.235, P=0.085). Even after adjustments for confounding risk factors, sRAGE was independently associated with VCS (β=-1.679, P=0.002). This study demonstrated that the circulating sRAGE level was inversely associated with VCS in HD patients independent of the S100A12 level and the severity of systemic inflammation.

Three-year variability in plasma concentrations of the soluble receptor for advanced glycation end products (sRAGE)

ObjectivesThe soluble receptor for advanced glycation end products (sRAGE) has been implicated in the development of diabetes-related vascular complications, but the variability of concentrations of sRAGE in the blood is unknown. The objective of this study was to characterize within-person three-year variability of plasma levels of sRAGE. Design and methodsWe measured sRAGE in plasma samples from 179 men and women in the community-based Atherosclerosis Risk in Communities (ARIC) Study at two time points, three years apart. We calculated correlation coefficients and the within-person coefficient of variation (CVw) to characterize variability in sRAGE. We compared these estimates to total cholesterol and white blood cell count (WBC) in the same participants. ResultsMean sRAGE concentrations at the two time points (mean time between measurements=2.9years) were 1096.2pg/mL and 990.2pg/mL, respectively (mean difference=−106.0pg/mL, p-value<0.001). The Pearson's correlation was 0.78 (Spearman's, 0.73). The intra-class correlation coefficient was 0.76 and the CVw was 26.6%. Compared to sRAGE, Pearson's and Spearman's correlations for total cholesterol (0.76 and 0.77) and white blood cell count (0.61 and 0.72) were similar, although CVw for both was lower (8.7% for cholesterol, 15.6% for WBC). Less than 4% of participants' values changed substantially (50% or greater) over the three-year interval. ConclusionsWe observed that sRAGE concentrations remained relatively stable over three years. Our findings suggest that a single measure of circulating sRAGE tracks well in a community-based population and could be a useful measure in clinical and epidemiologic studies of long-term risk.

Efficacy of alogliptin, a dipeptidyl peptidase‐4 inhibitor, on glucose parameters, the activity of the advanced glycation end product (AGE) – receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes

To examine the effects of alogliptin, a dipeptidyl peptidase-4 inhibitor, on glucose parameters, the advanced glycation end product (AGE)-receptor for AGE (RAGE) axis and albuminuria in Japanese type 2 diabetes patients. Sixty-one patients whose HbAlc ≥ 6.1% (mean age 64.7 years; 67% men; mean HbAlc 7.4%; 57% were pharmacologically treated) underwent blood and urine sampling and analysis before and after 12 weeks of treatment with alogliptin (25 mg once daily). Alogliptin treatment significantly reduced fasting glucose (160.3 mg/dL at baseline versus 138.0 mg/dL at 12 weeks), glycoalbumin (21.1% at baseline versus 18.9% at 12 weeks), HbAlc (7.4% at baseline versus 6.9% at 12 weeks), circulating soluble form of RAGE concentrations (847.3 pg/mL at baseline versus 791.4 pg/mL at 12 weeks) and urine albumin to creatinine ratio (31.6 mg/g Cr at baseline versus 26.5 mg/g Cr at 12 weeks), whereas 1,5-anhydroglucitol concentrations were significantly increased (7.5 µg/mL at baseline versus 11.6 µg/mL at 12 weeks; all P < 0.05). Circulating AGEs concentrations were reduced only in patients with baseline AGEs ≥7 U/mL (n = 33, from 8.2 U/mL to 7.2U /mL; p < 0.01) after alogliptin treatment. The treatment-induced change of soluble form of sRAGE concentrations was associated with changes of 1,5-anhydroglucitol and HbAlc concentrations (rho = -0.32 and 0.29, respectively). Meanwhile, the treatment-induced change of urine albumin to creatinine ratio was associated with a change in the fasting glucose concentration (rho = 0.25; all p < 0.05). During the intervention, alogliptin treatment was well tolerated without any hypoglycemia or side effects. Alogliptin treatment improved the AGE-RAGE axis and reduced albuminuria in Japanese type 2 diabetes patients.

S100A12 and Soluble Receptor for Advanced Glycation End Products Levels During Human Severe Sepsis

S100A12 is highly expressed, and serum levels correlate with individual disease activity in patients with inflammatory diseases. We here sought to determine the extent of S100A12 release and its soluble high-affinity receptor for advanced glycation end products (sRAGE) in patients with severe sepsis stratified to the three most common infectious sources (lungs, abdomen, and urinary tract) and to determine S100A12 and sRAGE concentrations at the site of infection during peritonitis. Two patient populations were studied: (a) 51 patients with sepsis due to (i) peritonitis (n = 12), (ii) pneumonia (n = 29), or (iii) urinary tract infection (n = 10); and (b) 17 patients with peritonitis. In addition, eight healthy humans were studied after intravenous injection of lipopolysaccharide (4 ng/kg). Compared with healthy volunteers, patients with severe sepsis displayed increased circulating S100A12 concentrations at day 0 (591.2 ± 101.0 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001) and at day 3 (637.2 ± 111.2 vs. 106.2 ± 15.6 ng/mL [control subjects], P < 0.0001). All three severe sepsis subgroups had elevated serum S100A12 concentrations at both time points (sepsis due to [i] peritonitis [393.5 ± 89.9 at day 0 and 337.9 ± 97.2 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.005 and P < 0.05, respectively]; [ii] pneumonia [716.9 ± 167.0 at day 0 and 787.5 ± 164.7 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, both P < 0.0001]; and [iii] urinary tract infection [464.2 ± 115.6 at day 0 and 545.6 ± 254.9 at day 3 vs. 106.2 ± 15.6 ng/mL, control subjects, P < 0.0001 and P < 0.05, respectively]). Remarkably, patients with sepsis due to pneumonia had the highest S100A12 levels (716.9 ± 167.0 and 787.5 ± 164.7 ng/mL at days 0 and 3, respectively). S100A12 levels were not correlated to either Acute Physiology and Chronic Health Evaluation II scores (r = -0.185, P = 0.19) or Sepsis-Related Organ Failure Assessment scores (r = -0.194, P = 0.17). Intravenous lipopolysaccharide injection in healthy humans elevated systemic S100A12 levels (peak levels at 3 h of 59.6 ± 22.0 vs. 12.4 ± 3.6 ng/mL; t = 0 h, P < 0.005). In contrast to S100A12, sRAGE concentrations did not change during severe sepsis or human endotoxemia. During peritonitis, S100A12 concentrations in abdominal fluid (12945.8 ± 4142.1 ng/mL) were more than 100-fold higher than in concurrently obtained plasma (121.2 ± 80.4 ng/mL, P < 0.0005), whereas sRAGE levels in abdominal fluid (148.8 ± 36.0 pg/mL) were lower than those in plasma (648.7 ± 145.6 pg/mL, P < 0.005) and did not increase. In conclusion, in severe sepsis, S100A12 is released systemically irrespective of the primary source of infection. During abdominal sepsis, S100A12 release likely predominantly occurs at the site of infection. Concentrations of its high-affinity sRAGE do not change during infection or human endotoxemia.

Soluble receptor for advanced glycation end products and risk of liver cancer

Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by the AGE/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample between 1985 and 1988. During follow-up beginning 5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentrations of sRAGE, CML-AGE, glucose, and insulin were measured in case subjects and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available in most cases and in a subset of the study population. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) adjusted for age, years of smoking, and body mass index. sRAGE and CML-AGE concentrations were inversely associated with liver cancer. Further adjustment for glucose and insulin or exclusion of case subjects with chronic HBV or HCV did not change the associations. Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and nonsmokers. (HEPATOLOGY 2013 ).

Plasma sRAGE and N‐(carboxymethyl) lysine in patients with CHF and/or COPD

Knowledge of the role of the receptor for advanced glycation end products (RAGE), particularly its soluble form (sRAGE), and of its advanced glycation end product (AGE) ligand, N-(carboxymethyl)lysine adducts (CML), is limited in chronic heart failure (CHF) and in chronic obstructive pulmonary disease (COPD). We evaluated whether the AGE/RAGE system is activated in stable CHF and COPD, and whether plasma sRAGE and CML levels are affected by clinical and functional parameters. We measured plasma levels of sRAGE and CML using a sandwich enzyme-linked immunosorbent assay (ELISA) in 143 subjects, aged ≥ 65 years, divided into five groups: 58 with CHF, 23 with COPD, 27 with CHF+COPD and 35 controls (17 healthy smokers and 18 healthy nonsmokers). Individuals with diabetes were excluded from the study. Plasma levels of sRAGE and CML were higher in CHF patients than in controls [sRAGE: 0.48 (0.37-0.83) vs. 0.42 (0.29-0.52) ng/mL, P = 0.01; CML: 1.95 (1.58-2.38) vs. 1.68 (1.43-2.00) ng/mL, P = 0.01]. By contrast, sRAGE and CML were not different between both COPD and CHF+COPD patients and controls (P > 0.05). N-terminal pro-brain natriuretic peptide (Nt-pro BNP) correlated with sRAGE, but not with CML, in the patient groups: CHF (r = 0.43, P < 0.001), COPD (r = 0.77, P < 0.0001) and CHF/COPD (r = 0.43, P = 0.003). Plasma levels of sRAGE and CML are increased in CHF, but not in COPD patients. The robust association between NT-pro BNP, a diagnostic and prognostic marker in CHF, and sRAGE concentrations might suggest a possible BNP pathway of amplification of inflammation via the AGE/RAGE system.

Soluble RAGE Plasma Levels in Patients with Coronary Artery Disease and Peripheral Artery Disease

The objective of the present study was define in a relatively large patient population with coronary artery disease (CAD) whether the concomitant presence of peripheral artery disease (PAD), which is known to convey additional cardiovascular risk, was associated with different circulating levels of sRAGE with respect to CAD alone and control subjects. Clinical and laboratory parameters including the ankle brachial index (ABI) and sRAGE (enzyme-linked immunosorbent assay kit) were investigated in 544 patients with angiographically documented CAD and 328 control subjects. 213/554 CAD patients (39%) showed an ABI <0.9 associated with typical symptoms (group CAD + PAD), whereas 331 patients were free from PAD. The concentration of plasma sRAGE was significantly lower (P < 0.0001) in CAD population, with and without PAD, than in control subjects. Among CAD patients, those with PAD showed lower levels of sRAGE. The distribution of the three groups (CAD, CAD + PAD, and controls) according to sRAGE tertiles showed that lower levels were more frequent in patients with CAD and CAD + PAD, whereas higher levels were more frequently found in controls. CAD patients presenting with PAD have lower sRAGE levels than CAD patients without peripheral atherosclerosis showing that stable atherosclerotic lesions in different vascular districts are inversely related to soluble decoy receptor sRAGE.

Relationship between sRAGE and eotaxin-3 with CRP in hypertensive patients at high cardiovascular risk

Cardiovascular disease (CVD) is the leading cause of death in Western countries and is highly prevalent in patients with kidney disease. Traditional risk factors for CVD often accompany kidney dysfunction, and chronic kidney disease per se is considered an additional risk factor. Risk stratification for CVD remains suboptimal even after the introduction of global risk assessment by various scores. This has prompted the search for novel markers of cardiovascular risk, and several biomarkers have been suggested as candidates, together with C-reactive protein (CRP). The objective of the present study was to investigate the relationship between novel biomarkers of vascular inflammation (soluble form of the receptor for advanced glycation end products [sRAGE] and eotaxin-3) with CRP in a population of hypertensive patients at high cardiovascular risk. Plasma sRAGE, high-sensitivity CRP (hs-CRP) and eotaxin-3 were measured in 399 hypertensive patients (265 men, mean age 58 ± 8 years)with diabetes mellitus, metabolic syndrome or organ damage. Plasma concentrations of sRAGE, eotaxin-3 and hs-CRP were not different between diabetic and nondiabetic subjects. Univariate analysis showed that plasma levels of sRAGE and eotaxin-3 were not associated with hs-CRP in either subgroup. Our study confirms the robust and widely studied role of CRP as an important marker of vascular inflammation. We also postulate the possible involvement of sRAGE and eotaxin, 2 novel biomarkers, in CVDs. On the basis of our results, we can put forward the hypotheses that hs-CRP, s-RAGE and eotaxin are reliable but unrelated cardiovascular risk markers.

Abstract 19: Soluble RAGE modestly inversely associated with liver cancer risk in male Finnish smokers.

Abstract Laboratory experiments suggest that activation of receptor for advanced glycation end products (RAGE) contributes to liver injury and blockade of RAGE with soluble RAGE (sRAGE) may mitigate the effects of RAGE activation. Epidemiologic studies examining sRAGE and advanced glycation end products (AGEs) in relation to liver cancer are sparse. Within a cohort of 29,133 Finnish male smokers who completed questionnaires and donated blood samples between 1985-1988, we conducted a case-cohort study examining the associations between serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE, the most abundant AGE in humans, in association with liver cancer. During follow-up that began 5 years after enrollment through April 2006, 145 liver cancer cases occurred. Serum levels of sRAGE, CML-AGE, glucose and insulin were measured in cases and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were also measured. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). Multivariate models were adjusted for age, years of smoking, and body mass index. Among subcohort participants, carbohydrate and sucrose intake increased across increasing tertiles of serum sRAGE (P-values ≤0.01). After adjusting for age, BMI and years of smoking, serum sRAGE concentration was inversely associated with liver cancer risk [continuous RR (95% CI): 0.86 (0.75-0.99), P-value=0.04]. Unexpectedly, serum CML concentration was also inversely associated with liver cancer risk [continuous RR (95% CI): 0.74(0.65-0.84), P-value &amp;lt;0.0001]. Further adjustment for serum glucose and insulin did not change the associations. The prevalence of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (anti-HBc) titers measured on 135 cases were 0.75% and 13%, respectively and 3% for hepatitis C exposure (anti-HCV). Exclusion of cases with chronic HBV or HCV did not change our results. Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and non-smokers. Citation Format: Kristin A. Moy, Li Jiao, Neal D. Freedman, Stephanie J. Weinstein, Rashmi Sinha, Jarmo Virtamo, Demetrius Albanes, Rachael Stolzenberg-Solomon. Soluble RAGE modestly inversely associated with liver cancer risk in male Finnish smokers. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 19.

Threshold serum concentrations of tumour necrosis factor alpha (TNFα) as a potential marker of the presence of microangiopathy in children and adolescents with type 1 diabetes mellitus (T1DM)

The aim of this study was to estimate the threshold serum concentrations of advanced glycation end products (AGEs) and their soluble receptors (sRAGE) as well as tumour necrosis factor alpha (TNFα), vascular endothelial growth factor(165) (VEGF(165)) and interleukin-12 (IL-12) in predicting the occurrence of microangiopathy in children and adolescents with type 1 diabetes mellitus (T1DM). We studied 88 children and adolescents (age range: 6-20 yrs) with T1DM and 32 control subjects (age range: 7-20 yrs). All study participants had their daily urinary albumin excretion, HbA1c and serum creatinine levels measured, and underwent an eye examination and 24-h blood pressure monitoring. Moreover, serum concentrations of AGEs, sRAGE, TNFα, VEGF(165) and IL-12 were measured. In order to calculate the threshold values of the studied parameters, the Receiver Operating Characteristic (ROC) curve analysis was used. The results of our study have shown that among all the studied parameters a discriminative ability was found for TNFα, VEGF(165), duration of the disease, serum AGEs concentrations and daily urinary albumin excretion. However, the highest value of the area under the ROC curve (AUC(ROC)) in predicting the occurrence of diabetic microangiopathy was found for serum TNFα concentrations with its threshold value of 1.7 pg/ml [AUC(ROC) = 0.88 (95% CI: 0.79-0.97)]. The sensitivity and specificity for this variable was at the level of 85.7% and 94.3%, respectively. In conclusion, according to our results serum TNFα concentrations over 1.7 pg/ml may point to the presence of diabetic microangiopathy in children and adolescents T1DM.

Intrafollicular soluble receptor for advanced glycation end products (sRAGE) and embryo quality in assisted reproduction

The developmental potential of human embryos has important implications in assisted reproduction and depends, among other factors, on oocyte competency. The receptor for advanced glycation end products (RAGE) is a member of the superfamily of immunoglobulin cell-surface molecules that are constitutively expressed during embryonic development. RAGE is down-regulated in homeostasis in adult life. This study measured the concentration of soluble RAGE (sRAGE) in follicular fluid obtained from the leading follicle after ovarian stimulation of 54 women undergoing intracytoplasmic sperm injection. Corresponding embryos and sRAGE concentrations in follicular fluid were evaluated and correlations were investigated by multi-adjusted regression analysis. High intrafollicular sRAGE concentrations predicted poor-quality embryos (n=45, OR=0.986; P=0.026), adjusted for patient age, body mass index and oocyte quality, showing an inverse association between intrafollicular sRAGE concentrations and embryo development.The developmental potential of human embryos has important implications in assisted reproduction, and it depends, among other factors, on oocyte competency. The receptor for advanced glycation end products (RAGE) is a molecule constitutively expressed during embryonic development, but it is down-regulated in adult life. RAGE is frequently associated with pro-inflammatory responses, and it is implicated as an underlying condition in immune disorders, cardiovascular diseases, diabetes, Alzheimer’s disease and cancer. In addition to activating the pro-inflammatory responses, RAGE down-regulates cellular defence mechanisms. The present study measured the concentrations of soluble RAGE (sRAGE) in follicular fluid samples obtained from leading follicles of women undergoing intracytoplasmic sperm injection (ICSI). This prospective cohort study included 54 patients undergoing ICSI, and follicular fluid samples were obtained from the leading follicle after ovarian stimulation. The corresponding embryos were evaluated and correlations with intrafollicular sRAGE concentrations were investigated using multi-adjusted regression analysis. We observed that high intrafollicular concentrations of sRAGE predicted poor embryo quality. Our findings suggest an association between high concentrations of intrafollicular sRAGE and poor embryo development following ovarian stimulation for ICSI.

Effects of Exercise on sRAGE Levels and Cardiometabolic Risk Factors in Patients with Type 2 Diabetes: A Randomized Controlled Trial

Low levels of soluble receptor for advanced glycation end-products (sRAGE) have been linked to systemic inflammation and vascular complications in patients with type 2 diabetes mellitus (T2DM). We examined the effects of exercise on sRAGE and its association with diverse cardiometabolic risk factors and indicators of atherosclerosis in patients with T2DM. Seventy-five patients with T2DM were randomized into a control group and an aerobic exercise group (60 min at moderate intensity, five times/wk for 12 wk). We evaluated sRAGE, energy expenditure, dietary energy intake, cardiorespiratory fitness, inflammatory markers, visceral fat area, pulse-wave velocity, and flow-mediated dilatation. Baseline sRAGE concentrations were independently associated with age, glycated hemoglobin, glucose, triglyceride, and high-density lipoprotein cholesterol levels (R2=0.244). After 12 wk of exercise training, the exercise group showed significantly decreased body weight, waist circumference, blood pressure, glycated hemoglobin, apolipoprotein B, and free fatty acid levels. Concurrently, cardiorespiratory fitness assessed by oxygen uptake at anaerobic threshold was improved, and body fat percentage and visceral fat area were significantly decreased in the exercise group, although pulse-wave velocity and flow-mediated dilatation were not changed. Furthermore, sRAGE levels were increased and high-sensitivity C-reactive protein levels were decreased in the exercise group but not in the control group. Percent change of sRAGE level was negatively correlated with that of high-sensitivity C-reactive protein during the study period (r=-0.27; P=0.019). Aerobic exercise increases sRAGE levels along with improvement of various cardiometabolic risk factors in patients with T2DM.

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

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. BAL was performed in 76 children, and BALF and plasma sRAGE levels were determined by enzyme-linked immunosorbent assay. 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. 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.

Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE

Objective: High mobility group box-1 (HMGB1) protein is an alarmin, a normal cell constituent, which is released into the extracellular environment upon cellular stress/damage and capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines; this may be modulated by the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objectives of this study were to determine whether: 1) clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age. Methods: Amniotic fluid samples were collected from the following groups: 1) mid-trimester (n = 45); 2) term with (n = 48) and without labor (n = 22) without intra-amniotic infection; and 3) term with clinical chorioamnionitis (n = 46). Amniotic fluid concentrations of HMGB1, sRAGE and esRAGE concentrations were determined by ELISA. Results: 1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than in those without this condition (clinical chorioamnionitis: median 3.8 ng/mL vs. term in labor: median 1.8 ng/mL, p = 0.007; and vs. term not in labor: median 1.1 ng/mL, p = 0.003); 2) in contrast, patients with clinical chorioamnionitis had a lower median sRAGE concentration than those without this condition (clinical chorioamnionitis: median 9.3 ng/mL vs. term in labor: median 18.6 ng/mL, p = 0.001; and vs. term not in labor median: 28.4 ng/mL, p < 0.001); 3) amniotic fluid concentrations of esRAGE did not significantly change in patients with clinical chorioamnionitis at term (clinical chorioamnionitis: median 5.4 ng/mL vs. term in labor: median 6.1 ng/mL, p = 0.9; and vs. term not in labor: median 9.5 ng/mL, p = 0.06); and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor (p = 0.4) and between women in the mid-trimester and those at term not in labor (mid-trimester: median 1.5 ng/mL; p = 0.2). Conclusion: An increase in the amniotic fluid HMGB1 concentration and a decrease in sRAGE were observed in clinical chorioamnionitis at term. This finding provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical chorioamnionitis at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations.

Relationship of Soluble RAGE and RAGE Ligands HMGB1 and EN-RAGE to Endothelial Dysfunction in Type 1 and Type 2 Diabetes Mellitus

Receptor for advanced glycation end-products (RAGE) plays the essential role in the pathogenesis of diabetic vascular complications. The aim of the study was to compare concentration of soluble RAGE and its ligands (EN-RAGE and HMGB1) with different biochemical parameters in Type 1 (T1DM) and Type 2 (T2DM) diabetes mellitus.Total number of 154 persons (45 T1DM, 68 T2DM, 41 controls) was examined and concentrations of sRAGE, EN-RAGE and HMGB1 were measured and compared to diabetes control, albuminuria, cell adhesion molecules and metalloproteinases (MMPs).Mean serum sRAGE concentration was higher in T1DM as compared to controls (1137±532 ng/l vs. 824±309 ng/l, p<0.01). Similarly, EN-RAGE was significantly higher in both diabetic groups (p<0.001) and HMGB1 concentrations were elevated in T2DM patients (p<0.01). Significant relationship was found between MMP9 and HMGB1 and EN-RAGE in diabetic patients. Inverse relationship was observed between MMP2 and MMP9 in both types of diabetic patients (r= - 0.602, p<0.002 and r= - 0.771, p<0.001). Significant positive correlation was found between sRAGE and ICAM-1, VCAM-1 or vWF (p<0.01 to p<0.001).We conclude that serum sRAGE and RAGE ligands concentrations reflect endothelial dysfunction developing in diabetes.

The receptor for advanced glycation endproducts and its ligands in patients with myasthenia gravis

ObjectiveMyasthenia gravis (MG) is a T- and B-cell mediated autoimmune disorder affecting the neuromuscular junction. The receptor for advanced glycation endproducts (RAGE) plays a role in the amplification of chronic inflammatory disorders and autoimmune diseases. We sought to investigate the role of RAGE and its ligands in the pathophysiology of MG. MethodsIn this cross-sectional study we enrolled 42 patients with MG and 36 volunteers. We employed enzyme-linked immunosorbent assays to determine the concentration of soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1) in serum of patients and volunteers. In a subpopulation of patients we measured the serum levels of endogenous secretory (es) RAGE and various RAGE ligands, such as S100B, S100A8 and advanced glycation endproducts (AGE-CML). Reported are means and standard error mean. ResultsWe found significantly reduced levels of the soluble receptors sRAGE and esRAGE in patients with MG compared to volunteers without MG (sRAGE [pg/ml] 927.2±80.8 vs. 1400.1±92.4; p<0.001; esRAGE [pg/ml] 273.5±24.6 vs. 449.0±22.4; p<0.001). Further categorization of patients with MG according to the distribution of muscle involvement revealed the following sRAGE concentrations: generalized MG 999.4±90.8 and ocular MG 696.1±161.8 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: generalized vs. ocular MG: p=0.264, generalized MG vs. control: p=0.008, ocular MG vs. control: p=0.001). In patients with detectable antibodies specific for acetylcholine receptors (Anti-AChR positive) the sRAGE concentration was 970.0±90.2 compared to those without (seronegative) 670.6±133.1 (vs. control; One-way ANOVA: p<0.001; Post hoc analysis: Pos vs. Neg.: p=0.418, Pos vs. control: p=0.003, Neg. vs. control: p=0.008). We next investigated the role of RAGE ligands in MG. The concentrations of RAGE ligands in patients with MG and controls were as follows: (HMGB1 [ng/ml] 1.7±0.1 vs. 2.1±0.2; p=0.058; S100B [pg/ml] 22.5±22.5 vs. 14.4±9.2; p=0.698; S100A8 [pg/ml] 107.0±59.3 vs. 242.5±103.6; p=0.347; and AGE-CML [ng/ml] 1100.8±175.1 vs. 1399.8±132.8; p=0.179). ConclusionsOur data suggest a role for the RAGE pathway in the pathophysiology of MG. Further studies are warranted to elucidate more about this immunological axis in patients with MG.

Microalbuminuria and sRAGE in High-Risk Hypertensive Patients Treated with Nifedipine/Telmisartan Combination Treatment: A Substudy of TALENT

Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR) are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products). In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE) plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.