Serum sRAGE Levels Research Articles

Evaluation of circulating sRAGE in osteoporosis according to BMI, adipokines and fracture risk: a pilot observational study

BackgroundOsteoporosis is a systemic metabolic disease based on age-dependent imbalance between the rates of bone formation and bone resorption. Recent studies on the pathogenesis of this disease identified that bone remodelling impairment, at the base of osteoporotic bone fragility, could be related to protein glycation, in association to oxidative stress. The glycation reactions lead to the generation of glycation end products (AGEs) which, in turn, accumulates into bone, where they binds to the receptor for AGE (RAGE). The aim of this study is to investigate the potential role of circulating sRAGE in osteoporosis, in particular evaluating the correlation of sRAGE with the fracture risk, in association with bone mineral density, the fracture risk marker FGF23, and lipid metabolism.ResultsCirculating level of soluble RAGE correlate with osteopenia and osteoporosis level. Serum sRAGE resulted clearly associated on the one hand to bone fragility and, on the other hand, with BMI and leptin. sRAGE is particularly informative because serum sRAGE is able to provide, as a single marker, information about both the aspects of osteoporotic disease, represented by bone fragility and lipid metabolism.ConclusionsThe measure serum level of sRAGE could have a potential diagnostic role in the monitoring of osteoporosis progression, in particular in the evaluation of fracture risk, starting from the prevention and screening stage, to the osteopenic level to osteoporosis.

AGER gene polymorphisms and soluble receptor for advanced glycation end product in patients with idiopathic pulmonary fibrosis.

The receptor for advanced glycation end product (RAGE) is a multiligand cell-surface receptor abundantly expressed in the lung. RAGE/ligand interaction has been postulated to participate in the pathogenesis of inflammatory diseases, while soluble RAGE (sRAGE) might act as a decoy receptor. A functional polymorphism rs2070600 in the gene coding RAGE (AGER) might modulate its receptor function. The aim of this study was to investigate the association of AGER polymorphisms and circulatory sRAGE with the development and progression of idiopathic pulmonary fibrosis (IPF). This study comprised 87 Japanese patients with IPF and 303 healthy controls. Seven tag polymorphisms in AGER were genotyped and their distributions were compared. We also measured serum sRAGE levels, and evaluated the correlations of sRAGE levels with AGER polymorphisms and the prognosis of the patients with IPF. The frequency of AGER rs2070600 genotype with minor allele was significantly higher in patients with IPF (OR = 1.84, 95% CI = 1.08-3.10). Additionally, the carriage of the rs2070600 minor allele and the presence of IPF were independently associated with reduced serum levels of sRAGE. Moreover, reduced sRAGE (≤471.8 pg/mL) was related to acute exacerbation of IPF and was an independent predictor of 5-year survival in patients with the disease (hazard ratio (HR) = 7.956, 95% CI = 1.575-53.34). These results suggest a possible association between a functional polymorphism in AGER and IPF disease susceptibility, and indicate a potential prognostic value of circulatory sRAGE.

Do Advanced Glycation End Products and Its Receptor Play a Role in Pathophysiology of Hypertension?

There is a close relationship between arterial stiffness and blood pressure. The studies suggest that the advanced glycation end products (AGEs) and its cell receptor (RAGE) are involved in the arterial stiffness in two ways: changes in arterial structure and vascular function. Plasma levels of AGEs and expression of RAGE are elevated, while the levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) are lowered in patients with hypertension (HTN). There is a positive correlation between plasma levels of AGEs and arterial stiffness, and an inverse association between arterial stiffness/HTN, and serum levels of sRAGE and esRAGE. Various measures can reduce the levels of AGEs and expression of RAGE, and elevate sRAGE. Arterial stiffness and blood pressure could be reduced by lowering the serum levels of AGEs, and increasing the levels of sRAGE. Levels of AGEs can be lowered by reducing the consumption of AGE-rich diet, short duration of cooking in moist heat at low temperature, and cessation of cigarette smoking. Drugs such as aminoguanidine, vitamins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, statins, and metformin inhibit AGE formation. Alagebrium, an AGE breakers reduces levels of AGEs. Clinical trials with some drugs tend to reduce stiffness. Systemic administration of sRAGE has beneficial effect in animal studies. In conclusion, AGE-RAGE axis is involved in arterial stiffness and HTN. The studies suggest that inhibition of AGEs formation, reduction of AGE consumption, blockade of AGE-RAGE interaction, suppression of RAGE expression, and exogenous administration of sRAGE may be novel therapeutic strategies for treatment of arterial stiffness and HTN.

An inverse association between serum soluble receptor of advanced glycation end products and hyperandrogenism and potential implication in polycystic ovary syndrome patients

BackgroundStudies found that AGE-RAGE system is closely related to insulin resistance and hyperandrogenemia, which are two core pathophysiological processes in polycystic ovary syndrome (PCOS). This study is to investigate the relationship among advanced glycation end-products/soluble receptor of advanced glycation end-products (AGEs/sRAGE) and anthropometric evaluation, homeostatic model assessment-insulin resistance (HOMA-IR), free androgen index (FAI) in reproductive-aged PCOS patients.MethodsOne hundred and forty-eight Chinese women with PCOS were enrolled in this study. Subgroups were divided according to body mass index (BMI), waist circumference (WC), quartile intervals of HOMA-IR and androgen levels. The relationships between AGEs/sRAGE and above clinical markers were assessed by Pearson’s correlation analyses.ResultsSerum AGEs showed a gradually increased tendency with BMI and WC. It reached statistical significant between the normal weight group (BMI < 24 kg/m2) and the obesity group (BMI ≥ 28 kg/m2) . The sRAGE levels gradually decreased with increasing BMI, WC, HOMA-IR and FAI respectively. Furthermore, the differences between each group were statistical significant. The correlation analysis showed a positive correlation between BMI and serum AGEs levels. On the contrary, the sRAGE levels showed significantly inverse correlations with BMI, WC, HOMA-IR and FAI. The optimal point of sRAGE for the presence of insulin resistance was 704.097 pg/ml by ROC curve analysis.ConclusionsAlong with the body fat accumulation, the serum levels of AGEs were increased, whereas, the serum levels of sRAGE were reduced in obese PCOS patients. The serum levels of sRAGE, which is a decoy receptor, dramatically decreased in the patients with more severe insulin resistant states and higher FAI, which might be a potential biomarker and a promising therapeutic target in the treatment of PCOS, especially in obese subjects.

Elevated endogenous secretory receptor for advanced glycation end products (esRAGE) levels are associated with circulating soluble RAGE levels in diabetic children.

Advanced glycation end products (AGEs) and the receptor for AGE (RAGE) play an important role in the development of diabetic vascular complications. This study aimed at investigating the relationship between the soluble form of RAGE (sRAGE), endogenous secretory RAGE (esRAGE), and pentosidine in childhood diabetes. The study included 18 children with type 1 diabetes mellitus (T1DM), 10 with type 2 DM (T2DM), and 22 age-matched, non-diabetic children (control). Serum sRAGE levels in the T1DM (2557.7 pg/mL) were significantly higher than both T2DM (1956.4 pg/mL) and control (1658.5 pg/mL). The circulating levels of esRAGE in T1DM and T2DM children were similar, but significantly higher than those of control. Serum pentosidine levels in the T1DM group were positively correlated with serum sRAGE and esRAGE levels, but not with anthropometric or biochemical measurements. The duration of diabetes and esRAGE levels were independent predictors of the circulating sRAGE levels. Unlike adults, children with diabetes exhibit high circulating esRAGE levels, and both sRAGE and esRAGE levels are correlated with pentosidine levels. These results suggest that circulating sRAGE and esRAGE in children may be surrogate markers for progressive glucose toxicity in pediatric patients with childhood-onset diabetes.

The Ser82 RAGE Variant Affects Lung Function and Serum RAGE in Smokers and sRAGE Production In Vitro.

IntroductionGenome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model.MethodsImmunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified.ResultsImmunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production.ConclusionsThis study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism.

Mouse Specific Cleavage-Resistant RAGE Splice Variant.

Receptor for Advanced Glycation Endproducts (RAGE), a transmembrane, multi-ligand, pattern recognition receptor, has been implicated in a range of inflammatory disease including diabetes, cancers, and cardiovascular disease (CVD) [1]. In addition to the full length receptor, soluble form of RAGE (sRAGE) has been shown to prevent the development of numerous pathologic states, and therefore highlights RAGE as an attractive therapeutic target [2–7]. sRAGE lacks the trans-membrane domain and is secreted to the extracellular milieu [6]. RAGE and sRAGE share the entire extracellular portion encompassing the V, C1 and C2 immunoglobulin-like domains (Fig 1). This feature renders sRAGE to function as a decoy that binds ligands and reduces the inflammatory signaling capacity of its membrane-bound counterpart [5, 7]. The importance of sRAGE is underscored by clinical cohort studies showing that serum sRAGE levels are correlated with clinical disease states including CVD, diabetes, cancer and various inflammatory disease states [6, 8].

Accumulation of Advanced Glycation End Products Involved in Inflammation and Contributing to Severe Preeclampsia, in Maternal Blood, Umbilical Blood and Placental Tissues

Objective: To investigate the expression of advanced glycation end products (AGEs) and the receptor for AGE (RAGEs) in maternal blood, umbilical blood and placental tissues in women with severe preeclampsia (sPE) as well as any association with inflammatory processes. Methods: The expressions of AGEs, RAGE, tumor necrosis factor-alpha (TNF)-α and vascular cell adhesion molecule-1 (VCAM)-1 in placental tissues were measured using immunohistochemistry. The levels of AGEs, RAGE, TNF-α and VCAM-1 in maternal blood, umbilical blood and placental extracts were assessed using enzyme-linked immunosorbent assays. Placental RAGE, TNF-α and VCAM-1 mRNA expression levels were determined by PCR. Placental AGEs, RAGE, TNF-α and VCAM-1 protein levels were determined by western blotting. Results: The levels of AGEs, TNF-α and VCAM-1 in the maternal tissues and umbilical blood were significantly higher in the sPE group than in the normal pregnancy (NP) controls (p < 0.05). The serum level of sRAGE in the umbilical blood was lower in the sPE group than in the NP controls (p < 0.05), while sRAGE was higher in the maternal blood of sPE than in the NP (p < 0.05). The maternal serum levels of AGEs were positively correlated with that of TNF-α and VCAM-1 in the maternal blood. There were no correlations between the levels of RAGE, TNF-α or VCAM-1 in maternal blood or umbilical serum. There were no correlations between the levels of sRAGE and TNF-α or VCAM-1 in maternal blood or umbilical serum. The levels of AGEs were positively correlated with those of TNF-α and VCAM-1 in placental lysates. Conclusion: AGEs and RAGE appear to act as important mediators in regulating the inflammatory pathways of preeclampsia.

Abstract LB-382: A prospective study of soluble receptor for advanced glycation end products and adiponectin and pancreatic cancer in postmenopausal women

Abstract Obesity is a recognized pancreatic cancer risk factor. Obesity-associated chronic inflammation and insulin resistance as well as western diet are associated with increased circulating levels of advanced glycation end products (AGEs) levels. When AGEs bind to their receptor (RAGE) on adipocytes, an inflammatory cascade is triggered and dysregulation of adipokines can occur. Soluble RAGE (sRAGE) mitigates this negative effect by acting as a decoy receptor for AGEs. In a nested case-control study in the prospective Women's Health Initiative study, we assessed the association between baseline levels of sRAGE and adiponectin and pancreatic cancer risk in post-menopausal women. Medical, lifestyle, diet data, anthropometric measurements and fasting blood were collected at baseline (1993-98). Serum sRAGE and adiponectin levels were immunoassay measured. With an average follow-up 14 years (thru 8/2013), we identified 494 incident cases with pancreatic cancer. Two controls were matched to each case by age, ethnicity, trial assignment and blood draw time (± 6 mos.). Multivariable conditional logistic regression analysis was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between sRAGE and adiponectin levels (quartile, Q) and pancreatic cancer after adjusting for waist-hip-ratio, diabetes, and dietary intake of alcohol, protein, saturated fat and carbohydrates. A total of 7.6% cases and 6.3% controls were current smokers. sRAGE was correlated with adiponectin among controls(r = 0.17, P &amp;lt;0.001). Higher sRAGE levels were associated with reduced risk of pancreatic cancer (aOR = 0.71, 95% CI: 0.56-0.90, P = 0.004 with sRAGE assessed as a continuous variable; aOR (Q4 vs Q1) = 0.75, 95% CI: 0.54-1.06, with P = 0.02 for trend across quartiles). Adiponectin was not associated with pancreatic cancer risk when assessed as a continuous variable (aOR = 1.008, 95% CI: 0.98-1.02); however, women with highest adiponectin levels had reduced risk of pancreatic cancer (aOR Q4 vs Q1 = 0.73, 95% CI: 0.51-1.04, P = 0.06 for trend). Women with higher levels of both sRAGE and adiponectin (above their respective medians) had greatest risk reduction (aOR = 0.59, 95% CI: 0.42-0.82) compared with women with lower levels of both biomarkers(P for interaction = 0.15). Consistent with our prior work in Finnish male smokers, we found an inverse association between pre-diagnostic sRAGE and risk of incident pancreatic cancer. We also identified a potential effect modification of adiponectin by sRAGE in postmenopausal women. The role of the RAGE pathway in obesity-related pancreatic cancer needs further investigation. Citation Format: Donna L. White, Ron Hoogeveen, Kathryn Royse, Liang Chen, Lesley Tinker, Tom Rohan, Eric Whitsel, Hashem B. El-Serag, Li Jiao. A prospective study of soluble receptor for advanced glycation end products and adiponectin and pancreatic cancer in postmenopausal women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-382.

The diagnostic utility and tendency of the soluble receptor for advanced glycation end products (sRAGE) in exudative pleural effusion.

The soluble receptor for advanced glycation end products (sRAGE) may have an inflammatory or homeostatic function in lung tissue. The aim of this study was to assess the usefulness of sRAGE as a diagnostic marker for exudative pleural effusions, which are common manifestations of a variety of diseases. Patients with an undiagnosed pleural effusion were prospectively enrolled between January 2013 and January 2015. Samples of blood and pleural fluid were centrifuged and the supernatant stored at -70 °C. The levels of sRAGE in serum and pleural fluid were determined using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. In total 47 patients, 21 patients were diagnosed with a tuberculous effusion, and the groups diagnosed with parapneumonic or malignant effusions comprised 13 patients each. The serum sRAGE levels for tuberculosis were significantly elevated [median, 1,291 pg/mL; interquartile range (IQR), 948-1,711 pg/mL] when compared with those for both pneumonia (median, 794 pg/mL; IQR, 700-1,255 pg/mL) and lung cancer (median, 886 pg/mL; IQR, 722-1,285 pg/mL) (P=0.029). The pleural sRAGE levels for pneumonia (median, 1,763 pg/mL; IQR, 1,262-4,431 pg/mL) were lower than those for both tuberculosis (median, 5,081 pg/mL; IQR, 3,300-6,004 pg/mL) and lung cancer (median, 4,936 pg/mL; IQR, 3,282-7,018 pg/mL) (P=0.009) The receiver operating characteristic (ROC) curve analysis selected 896 pg/mL as the best cutoff value in the sRAGE serum level for tuberculosis [sensitivity, 86%; specificity 58%; area under the curve (AUC) =0.727, P=0.008]. For the pleural effusion sRAGE level, the ROC curve analysis selected 2,231 pg/mL as the best cutoff value for pneumonia (sensitivity, 91%; specificity, 62%, AUC =0.792, P=0.002). Among patients with exudative effusion, pleural and serum sRAGE measurements may be useful supportive diagnostic tools in the evaluation of ambiguous pleural effusion. Furthermore, the behavior of sRAGE in the serum and pleural fluid of various pulmonary diseases suggests that sRAGE may be linked to the chronic process of lung damage and inflammation rather than acute bacterial infection.

Reduced soluble RAGE is associated with disease severity of axonal Guillain-Barré syndrome.

Soluble receptor for advanced glycation end products (sRAGE) is an anti-inflammatory factor that mitigates the proinflammatory effects of high mobility group box 1 (HMGB1). The aim of this study was to investigate whether Guillain-Barré syndrome (GBS)-related inflammation are mediated by sRAGE and HMGB1. We measured serum sRAGE, HMGB1, IL-6, and TNF-α levels in 86 patients with GBS and analysed associations between sRAGE or HMGB1 and clinical variables in these subjects. In addition, we determined cerebrospinal fluid sRAGE and HMGB1 levels in a cross-sectional study of 50 patients with GBS who had matched serum samples. We found serum sRAGE levels in patients with the acute motor axonal neuropathy (AMAN) subtype of GBS, but not other subtypes, were significantly lower than those in healthy controls, and were significantly correlated with GBS disability score and Erasmus GBS outcome score, while serum HMGB1, IL-6, and TNF-α levels in all subtypes of GBS were significantly higher than those in healthy controls. Moreover, increased sRAGE levels and decreased HMGB1 levels after treatment were observed. Our results showed that serum sRAGE may be a useful biomarker for inflammation in the AMAN GBS subtype, while HMGB1 may be related to the inflammatory process across all types of GBS.

Advanced glycation end products (AGEs) and its receptors in the pathogenesis of hyperthyroidism.

Oxidative stress has been implicated in the pathogenesis of hyperthyroidism and its complications. Interaction of advanced glycation end products (AGEs) with receptor RAGE (receptor for AGEs) generates reactive oxygen species. Soluble receptor for AGEs (sRAGE) competes with RAGE for binding with AGEs and attenuates the generation of ROS. Low levels sRAGE and high levels AGEs would generate more ROS leading to hyperthyroidism and its complications. The objectives are to determine if levels of serum sRAGE are low and the levels of AGEs and AGEs/sRAGE are high in patients with hyperthyroidism. The study subjects comprised of 33 patients with hyperthyroidism and 20 controls. Levels of serum sRAGE were lower, while that of AGEs and AGEs/sRAGE were higher in patients compared to controls, being significant only for sRAGE and AGEs/sRAGE. When the levels of sRAGE, AGEs, and AGEs/sRAGE were assessed for hyperthyroidism associated with different diseases, the levels of sRAGE were lower in Hashimoto disease, and levels of AGEs were higher in patients with Graves' disease compared to control. The levels of AGEs/sRAGE were elevated in an all except patients with Hashimoto disease. The levels of AGEs, sRAGE, or AGEs/RAGE were not correlated with age, weight, and blood pressures except systolic pressure which was inversely correlated with sRAGE. The levels of sRAGE were negatively correlated with AGEs and AGEs/sRAGE. The levels of AGEs/sRAGE were positively correlated with AGEs. In conclusion, low levels of sRAGE, and high levels of AGEs and AGEs/sRAGE are risk biomarkers in the pathogenesis hyperthyroidism and its complications.

Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm.

Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iβ, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.

Atherosclerosis and the Hypercholesterolemic AGE-RAGE Axis.

Background Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis. We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis. Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE. Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed. Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low-density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects. Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis; however, more research must be conducted.

RAGE and AGEs in Mild Cognitive Impairment of Diabetic Patients: A Cross-Sectional Study.

ObjectiveReceptor for advanced glycation end products (AGEs; RAGE) binds to both AGEs and amyloid-beta peptides. RAGE is involved in chronic complications of type 2 diabetes and Alzheimer’s disease. We aimed to investigate the roles of RAGE, AGEs and the Gly82Ser polymorphism of RAGE in mild cognitive impairment (MCI) among type 2 diabetes patients.MethodsOf the 167 hospitalized type 2 diabetes patients recruited, 82 satisfied the diagnostic criteria for MCI, and 85 matched control individuals were classified as non-MCI. Demographic data were collected, and the soluble RAGE (sRAGE) concentrations, serum AGE-peptide (AGE-P) levels, RAGE Gly82Ser genotype and neuropsychological test results were examined.ResultsThe MCI group exhibited a decreased sRAGE level (0.87±0.35 vs. 1.05±0.52 ng/ml, p<0.01) and an increased serum AGE-P level (3.54±1.27 vs. 2.71±1.18 U/ml, p<0.01) compared with the control group. Logistic regression analysis indicated that each unit reduction in the sRAGE concentration increased the MCI risk by 54% (OR 0.46[95% CI 0.22–0.96], p = 0.04) and that each unit increase in the AGE-P level increased the MCI risk by 72% in the type 2 diabetes patients (OR 1.72[95% CI 1.31–2.28], p<0.01). The serum sRAGE level was negatively correlated with the score on the trail making test-B (TMT-B) (r = -0.344, p = 0.002), which indicates early cognitive deficits related to diabetes. Moreover, the AGE-P level was positively correlated with multiple cognitive domains (all p<0.05). No significant differences in the neuropsychological test results or serum RAGE concentrations between the different RAGE genotypes or in the RAGE genotype frequencies between the MCI and control groups were identified (all p>0.05).ConclusionsThe RAGE pathway partially mediates AGE-induced MCI in diabetic patients. The serum AGE-P level may serve as a serum biomarker of MCI in these individuals, and sRAGE represents a predictor and even a potential intervention target of early cognitive decline in type 2 diabetes patients.Trial registrationAdvanced Glycation End Products Induced Cognitive Impairment in Diabetes: BDNF Signal Meditated Hippocampal Neurogenesis ChiCTR-OCC-15006060

Serum soluble RAGE level inversely correlates with left ventricular hypertrophy in essential hypertension patients.

Soluble receptor for advanced glycation end-products (sRAGE) acts as a decoy to prevent interaction between RAGE and its pro-inflammatory ligands. sRAGE levels have been found to decrease in chronic inflammatory diseases, including hypertension. However, few data have been reported concerning the association between serum sRAGE levels and hypertensive left ventricular hypertrophy (LVH). Fasting blood samples were obtained from 209 essential hypertensive patients, and sRAGE levels were measured using a commercially available double-sandwich enzyme-linked immunosorbent assay kit. All patients underwent complete transthoracic echocardiographic examination. LVH was defined as a left ventricular mass index >115 g/m(2) for men and >95 g/m(2) for women. Eighty-one hypertensive patients (38.76%) were categorized in the LVH(+) group. Age (P = 0.009), hypertension duration (P = 0.013), triglyceride levels (P = 0.028), and systolic blood pressure (P = 0.026) were higher, and sRAGE and high-density lipoprotein cholesterol levels were lower in the LVH(+) group compared with the LVH(-) group. Multivariate logistic regression analysis showed that sRAGE level [odds ratio (OR) = 0.916; 95% confidence interval (CI) = 0.864-0.984; P = 0.003], hypertension duration (OR = 1.024; 95%CI = 1.003-1.052; P = 0.027), and triglyceride level (OR = 1.017; 95%CI = 1.005-1.039; P = 0.018) were independent predictors of LVH in hypertensive patients. In conclusion, serum sRAGE level was inversely associated with LVH in hypertensive patients.

Human soluble receptor for advanced glycation end products and tumor necrosis factor-α as gingival crevicular fluid and serum markers of inflammation in chronic periodontitis and type 2 diabetes.

The present study aimed to evaluate the levels of soluble receptor for advanced glycation end products (sRAGE) and tumor necrosis factor-α (TNF-α) in serum and gingival crevicular fluid (GCF) in chronic periodontitis (CP) patients with and without type 2 diabetes mellitus (T2DM). A total of 70 subjects were divided into four groups: group 1 (n = 15; subjects with healthy periodontium); group 2 (n = 20; CP patients); group 3 (n = 20; CP patients with T2DM); and group 4 (n = 15; CP patients without T2DM). The serum and GCF levels of human sRAGE and TNF-α were assessed using enzyme-linked immunosorbent assay and correlated with clinical parameters, including probing depth, gingival index and clinical attachment level. Both sRAGE and TNF-α levels varied with the inflammatory state of the patient; the highest levels of sRAGE were seen in group 1, whereas the lowest levels in group 3 (P < 0.05). Conversely, TNF-α levels were found to be the highest in group 3 and lowest in group 1 (P < 0.05). Thus, human sRAGE and TNF-α can be considered as possible GCF and serum markers of inflammatory activity in CP and T2DM.(J Oral Sci 58, 547-553, 2016).

Receptor for advanced glycation endproducts in pediatric sepsis: a pilot study

Background Sepsis in pediatric patients is still a leading cause of morbidity and mortality. Aim The aim of the study was to determine whether the serum level of receptor for advanced glycation endproducts (RAGEs) can be used as a potential diagnostic and prognostic marker in septic children. Patients and methods A pilot study was conducted on pediatric intensive care unit patients who had clinical evidence of sepsis over a 1-year period. Forty patients were enrolled in the study within the first 24 h after onset of sepsis; they were classified according to 28-day mortality into survivors and nonsurvivors. Complete blood count, erythrocyte sedimentation rate, C-reactive protein, and soluble form of RAGE (sRAGE) were measured. Bacterial cultures from suitable body fluids were prepared. Results There was a significantly higher mean serum sRAGE level among septic patients compared with controls (P=0.001); the level was higher in nonsurvivors compared with survivors (P=0.001). A cutoff value of 1325 pg/ml for serum sRAGE showed a sensitivity of 89.2% and a specificity of 78.3%. There were positive correlations with C-reactive protein and Pediatric Risk of Mortality III, and no correlation with bacterial culture. Multivariate logistic regression analysis showed that sRAGE level and leukocytic count were significant markers in the diagnosis of sepsis (P=0.047 and 0.001, respectively). sRAGE level and Pediatric Risk of Mortality III score were significant parameters in sepsis prognosis (P=0.019 and 0.043, respectively). Conclusion Serum sRAGE can be used as a diagnostic and prognostic marker in pediatric sepsis, especially in those with a negative blood culture.

Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

Abstract 9844: Endothelial Function is Impaired in Subjects With Increased Ratio of Serum Levels of AGEs to Soluble Form of RAGE

Introduction: Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE and vascular function. Methods: We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. Results: Univariate regression analysis revealed that FMD correlated with age (ρ=-0.38, P&lt;0.01), body mass index (ρ=-0.28, P&lt;0.01), systolic blood pressure (ρ=-0.44, P&lt;0.01), diastolic blood pressure (ρ=-0.46, P&lt;0.01), heart rate (ρ=-0.29, P&lt;0.01), triglycerides (ρ=-0.37, P&lt;0.01), high-density lipoprotein cholesterol (ρ=0.19, P&lt;0.05), glucose (ρ=-0.20, P&lt;0.05), smoking pack-years (ρ=-0.32, P&lt;0.01), nitroglycerine-induced vasodilation (ρ=0.40, P&lt;0.01), serum levels of AGEs (ρ=-0.34, P&lt;0.01) and sRAGE (ρ=0.20, P&lt;0.05), and ratio of AGEs to sRAGE (ρ=-0.38, P&lt;0.01). Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD (β=-0.22, P=0.03), while serum level of AGEs alone (β=-0.14, P=0.13) or sRAGE alone (β=0.13, P=0.15) was not associated with FMD. Conclusions: These findings suggest that sRAGE may have a counter-regulatory mechanism that is activated to counteract the vasotoxic effect of the AGEs-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.