sRAGE Levels Research Articles

Higher sRAGE Levels Predict Mortality in Frail Older Adults with Cardiovascular Disease

Introduction: The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association. Methods: We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up. Results: In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09–2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18–3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71–3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value. Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.

Association Between Soluble Receptor for Advanced Glycation End Product and Endogenous Secretory Soluble Receptor for Advanced Glycation End Product Levels and Carotid Atherosclerosis in Diabetes: A Systematic Review and Meta-Analysis

BackgroundThe soluble receptor for advanced glycation end product (sRAGE) and endogenous secretory RAGE (esRAGE) are novel biomarkers that are associated with vascular disease. We carried out a systematic review to provide a more complete picture of sRAGE, esRAGE, carotid atherosclerosis and cardiovascular disease (CVD) in patients with diabetes. MethodsWe searched the Cochrane Library, PubMed and Embase databases. Systematic review best practices were followed, and study quality was assessed. ResultsUltimately, 11 studies met all the inclusion criteria. Meta-analysis indicated that esRAGE was not significantly lower in patients with type 1 diabetes (T1D) (standardized mean difference [SMD], −0.76; 95% confidence interval [CI], −1.57 to 0.05; I2=90%; p=0.002), whereas it was significantly lower in patients with type 2 diabetes (T2D) (SMD, −1.08; 95% CI, −1.53 to −0.62; I2=80%; p=0.006). Meta-analysis suggested that sRAGE levels were not significantly lower or higher in T1D (SMD, 0.06; 95% CI, −0.14 to 0.26; I2=38%; p=0.20) or T2D (SMD, 0.00; 95% CI, −0.26 to 0.26; I2=0.00%; p=1.00) patients. The level of esRAGE was inversely correlated with carotid intima-media thickness (IMT) in T2D patients, whereas there was a contrasting relationship between sRAGE and carotid IMT in T1D patients. Higher sRAGE was associated with cardiovascular events. ConclusionOur meta-analysis showed that circulating esRAGE was lower and inversely correlated with IMT in T2D patients.

The receptor for advanced glycation end product (RAGE) pathway in COVID-19

Introduction Coronavirus disease-2019 (COVID-19) with lung involvement frequently causes morbidity and mortality. Advanced age appears to be the most important risk factor. The receptor for advanced glycation end-product (RAGE) pathway is considered to play important roles in the physiological aging and pathogenesis of lung diseases. This study aimed to investigate the possible relationship between COVID-19 and RAGE pathway. Materials and methods This study included 23 asymptomatic patients and 35 patients with lung involvement who were diagnosed with COVID-19 as well as 22 healthy volunteers. Lung involvement was determined using computed tomography. Serum soluble-RAGE (sRAGE) levels were determined using enzyme-linked immunosorbent assay. Results The sRAGE levels were significantly higher in the asymptomatic group than in the control group. Age, fibrinogen, C-reactive protein, and ferritin levels were higher and the sRAGE level was lower in the patients with lung involvement than in the asymptomatic patients. Conclusions In this study, patients with high sRAGE levels were younger and had asymptomatic COVID-19. Patients with low sRAGE levels were elderly patients with lung involvement, which indicates that the RAGE pathway plays an important role in the aggravation of COVID-19.

Association analysis of 374T/A (rs1800624) receptor for advanced glycation end-products (RAGE) gene polymorphism with diabetic retinopathy in Pakistani patients.

Objectives:to determine the relationship of 374T/A (rs1800624) polymorphism in the gene encoding RAGE with Type-2 diabetes mellitus (T2DM), diabetic retinopathy (DR) and serum soluble RAGE (sRAGE) level in Pakistani patients.Methods:A case-control study, conducted from January 2017 to December 2018, involving 150 healthy controls (HC), 150 T2DM patients with no retinopathy (DNR) and 150 DR patients diagnosed by coloured fundus photography. Tetra-primer amplification refractory mutation system – polymerase chain reaction (T-ARMS-PCR) was used for genotyping. Serum sRAGE levels were measured by enzyme-linked immunosorbent assays (ELIZA).Results:The frequency of TT, TA and AA genotypes of rs1800624 polymorphism were: 92.7%, 6%, 1.3% in HC, 80%, 17.3%, 2.7% in DNR and 76.7%, 19.3%, 4.3% in DR groups. Heterozygous TA genotype and mutant A allele showed significant association with diabetes and DR vs HC. In dominant model, mutant allele showed significant association with DNR and DR vs HC. No significant association of rs1800624 was detected with DR and its sub-groups, non-proliferative DR (NPDR) and proliferative DR (PDR) vs DNR. Dividing NPDR into mild, moderate and severe, heterozygous TA genotype showed significant association with moderate and severe NPDR vs DNR. In DNR and DR groups, TA genotype was significantly associated with raised sRAGE.Conclusion:rs1800624 RAGE gene polymorphism might be a risk factor for T2DM and NPDR in Pakistani patients. Raised sRAGE levels have a positive correlation with PDR and are associated with heterozygosity of rs1800624 polymorphism in DNR and DR groups

Significance of combined application of biomarkers in the diagnosis and prognosis assessment of patients with acute respiratory distress syndrome

To explore the clinical significance of the combined detection of Clara cell secretory protein 16 (CC16) and soluble receptor for advanced glycation end product (sRAGE) in the diagnosis and prognosis of acute respiratory distress syndrome (ARDS). 100 ARDS patients admitted to the intensive care unit (ICU) of Chu Hsien-I Memorial Hospital of Tianjin Medical University from July 2019 to September 2020 were enrolled as the ARDS group, and 100 non-ARDS patients admitted to the ICU during the same period were enrolled as the control group. The general information, vital signs, blood gas analysis, serum CC16 and sRAGE levels, duration of mechanical ventilation, length of ICU stay and prognosis during hospitalization were collected. The receiver operating characteristic (ROC) curve was drawn and the area under ROC curve (AUC) was calculated to evaluate the clinical value of CC16 and sRAGE lonely or combination in the diagnosis and prognosis of ARDS. The duration of mechanical ventilation in the ARDS group was significantly longer than that in the non-ARDS group (days: 15.44±3.04 vs. 12.61±3.73, P < 0.01), and the hospitalization mortality was higher (38.0% vs. 9.0%, P < 0.01), but there was no significant difference in gender, age, body mass index (BMI), acute physiology and chronic health evaluation II (APACHE II) score or the length of ICU stay between the two groups. There were 62 ARDS patients survived and 38 ARDS patients died during hospitalization. The APACHE II score of the death group was significantly higher than that of the survival group (23.55±2.83 vs. 19.40±4.10, P < 0.01), but there was no significant difference in age, BMI, oxygenation index, mean arterial pressure, duration of mechanical ventilation or the length of ICU stay between the two groups. The serum levels of CC16 and sRAGE in the ARDS group were significantly higher than those in the non-ARDS group [CC16 (mg/L): 38.78±14.70 vs. 21.87±2.45, sRAGE (pg/L): 2 470.95±288.70 vs. 2 013.22±131.15, both P < 0.01]; and the serum levels of CC16 and sRAGE of ARDS patients in the death group were significantly higher than those in the survival group [CC16 (mg/L): 42.02±10.81 vs. 30.52±9.47, sRAGE (pg/L): 2 638.34±324.07 vs. 2 279.91±163.70, both P < 0.01]. ROC curve showed that the AUC of CC16 and sRAGE in the diagnosis of ARDS alone were 0.859 [95% confidence interval (95%CI) was 0.808-0.911] and 0.821 (95%CI was 0.762-0.879), and the best cut-off values were 25.76 mg/L and 2 203.00 pg/L, respectively; the AUC of combined detection of CC16 and sRAGE was 0.932 (95%CI was 0.900-0.965) with the sensitivity of 89.0% and the specificity of 87.6%. The AUC of CC16 and sRAGE in predicting the death of patients with ARDS during hospitalization were 0.747 (95%CI was 0.651-0.843) and 0.819 (95%CI was 0.737-0.902), and the best cut-off values were 32.95 mg/L and 2 554.50 pg/L, respectively; the AUC of combined detection of CC16 and sRAGE was 0.900 (95%CI was 0.828-0.972) with the sensitivity of 88.7% and the specificity of 84.5%. Serum CC16 and sRAGE have clinical value for the diagnosis and prognosis of ARDS. The combined detection of them is superior to individual detection for early prediction of ARDS and prognosis.

Relevance of Circulating Nucleosomes, HMGB1 and sRAGE for Prostate Cancer Diagnosis.

Evasion from cell death occurs in prostate cancer (PCa). We verified whether serum levels of cell death markers can have diagnostic value in PCa. A total of 233 men scheduled for prostate biopsy [prostate specific antigen (PSA) level: 2-10 ng/ml] were enrolled. Serum nucleosomes, nucleosomes containing the H3 histone (H3), high mobility group box 1 (HMGB1), and soluble receptor for advanced glycation end products (sRAGE) were analyzed by enzyme immunoassays. There were no differences (p>0.05) in nucleosomes, H3, and sRAGE levels between patients with and without PCa or clinically significant PCa (csPCa). HMGB1 had lower levels in PCa patients (p=0.023) and was a predictor of PCa (p=0.047), but not of csPCa (p=0.180). In patients with critical PSA levels between 2-10 ng/ml, HMGB1 had some diagnostic value for overall PCa detection, but it was not predictive of csPCa. Nucleosomes, H3 and sRAGE did not discriminate between PCa or csPCa and controls.

Comparative evaluation of Salivary-Soluble Receptor for Advanced Glycation End Product (sRAGE) levels among betel chewers and chronic periodontitis patients

Background: Advanced glycation end products (AGE) are heterogeneous groups of molecules formed from the nonenzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. Activation of receptor for advanced glycation end products (RAGE) by ligands in a variety of cell types and tissues may play a role in oral-systemic associations. The aim of the study is to estimate the salivary-soluble RAGE (sRAGE) levels in betel chewers and compare with salivary sRAGE levels of chronic periodontitis and normal healthy controls. Methods: Detailed case history and clinical examination was done for the study participants based on the inclusion and exclusion criteria. Study participants were grouped as Group I (chewers), Group II (chronic periodontitis), and Group III (normal controls). Unstimulated saliva samples were collected and salivary sRAGE levels were calculated using the sandwich ELISA technique. Results: Individuals with pan chewing habits have demonstrated increase in salivary sRAGE compared to chronic periodontitis and normal controls. Conclusions: Understanding AGE formation and biochemistry, cellular receptors for AGE, and AGE-induced effects on extracellular and intracellular functions will serve to expedite the process of finding effective therapies that block the excessive accumulation of these species and their interaction with the signal transduction receptor RAGE.

Targeting AGEs pathway in delayed diabetic wound healing

Introduction: Diabetic complications as peripheral neuropathy and delayed wound healing affect patient’s quality of life and may lead to amputation. Several mechanisms are involved in mediating these complications including accumulation of Advanced Glycation End Products (AGEs) and the subsequent state of inflammation which were investigated in the current study. Methos: A wound of fixed size was induced in STZ-diabetic rats and the effect of diabetes and treatment with glimepiride, α-lipoic acid and pyridoxamine on the levels of glucose, insulin, HbA1c, AGEs, RAGE, sRAGE, TNF-α and adiponectin were investigated. Also the latency time in the hotplate test and wound healing were quantified at different time points. Results: Our results have shown that STZ induced a condition of diabetes (elevated glucose, HbA1c, and reduced insulin), enhanced AGEs signaling (elevated AGEs, RAGE, and reduced sRAGE) and inflammation (elevated TNF-α and reduced adiponectin), accompanied by hyperalgesia and delayed wound healing, while all treatments were able to ameliorate most of these effects. Conclusion: These results confirm the involvement of AGEs signaling in mediating diabetic complications and suggest their possible use in the standard therapy for diabetic patients.

Advanced Glycation End Products (AGE) and Soluble Forms of AGE Receptor: Emerging Role as Mortality Risk Factors in CKD.

Advanced glycation end-products (AGE) can promote chronic kidney disease (CKD) progression and CKD-related morbidities. The soluble receptor for AGE (sRAGE) is a potential biomarker of inflammation and oxidative stress. Here, we explored the role of AGE, glycated albumin, sRAGE and its different forms, cRAGE and esRAGE, as prognostic factors for mortality in 111 advanced CKD patients. The median follow-up time was 39 months. AGE were quantified by fluorescence, sRAGE and its forms by ELISA. Malnutrition was screened by the Malnutrition Inflammation Score (MIS). The Cox proportional hazards regression model was used to assess the association of variables with all-cause mortality. Mean levels of sRAGE, esRAGE and cRAGE were 2318 ± 1224, 649 ± 454 and 1669 ± 901 pg/mL. The mean value of cRAGE/esRAGE was 2.82 ± 0.96. AGE were 3026 ± 766 AU and MIS 6.0 ± 4.7. eGFR correlated negatively with AGE, sRAGE, esRAGE and cRAGE, but not with cRAGE/esRAGE. Twenty-eight patients died. No difference was observed between diabetic and non-diabetic patients. Starting dialysis was not associated with enhanced risk of death. AGE, esRAGE and cRAGE/esRAGE were independently associated with all-cause mortality. AGE, esRAGE and cRAGE/esRAGE may help to stratify overall mortality risk. Implementing the clinical evaluation of CKD patients by quantifying these biomarkers can help to improve patient outcomes.

Plasma amyloid‐β dynamics are regulated by the sleep‐wake cycle

AbstractBackgroundIt has been reported that sleep is an important physiological process and conducive to the elimination of brain metabolites and the recovery of brain function. Growing evidence suggested that sleep disorders were related to increased risk of AD and Aβ accumulation in the brain. Although peripheral Aβ clearance is associated with brain Aβ deposition, but the relationship between sleep‐wake cycle and plasma Aβ levels is unclear.MethodThirty cognitively normal healthy adults (aged 29.07 ± 8.12), sixteen males (53.33%), were recruited. Participants underwent normal sleep and peripheral blood samples were collected every three hours between 20:00 and 8:00 the next day. Plasma Aβ40, Aβ42, total tau, phosphorylated tau 181 (P‐tau), soluble low‐density lipoprotein receptor‐related protein (sLRP1) and soluble receptors for advanced glycation end products (sRAGE) levels were measured using ELISA kits.ResultPlasma Aβ40 concentration at 5:00 decreased significantly compared with plasma level at 23:00 (p=0.041), and there is a dynamic tendency of decreasing after sleep onset and increasing after awake, which is in accordance with the sleep‐wake cycle. Furthermore, Aβ40 and Aβ42 levels were positively correlated with plasma sLRP1 (Aβ40: r=0.1791, p=0.0283; Aβ42: r=0.1780, p=0.0293). However, there was no significant dynamic change in Aβ42, Tau, P‐tau, Tau, sLRP1 and sRAGE levels in twelve hours.ConclusionPlasma Aβ40 dynamics are regulated by the sleep‐wake cycle, and it may play a positive feedback regulating role in sLRP1 level.

Advanced glycation end products, their receptor and the risk of dementia in the general population: A prospective cohort study

AbstractBackgroundAdvanced glycation end products (AGEs) and their receptor (RAGE) are implicated in the pathophysiology of dementia and potentially underlie the relation between diabetes and neurodegeneration. We determined the link between two proteins involved in the AGE‐RAGE system, namely Extracellular Newly identified RAGE binding protein (EN‐RAGE) and the soluble form of RAGE (sRAGE), and dementia prevalence and incidence. Additionally, we assessed the association between skin auto fluorescence (SAF), a proxy for AGEs tissue accumulation, and cognition.MethodWithin the prospective Rotterdam Study, plasma EN‐RAGE and sRAGE were measured in 1208 participants (mean age 74.1 (standard deviation (SD) 7.7); 57.5% women). Participants were categorized into tertiles, to compare participants with high, intermediate and low concentrations, with the lowest tertile as the reference. Associations of SAF, measured in 3009 participants (mean age 72.3 (SD 9.4); 56.4% women), and cognition were assessed using linear models. We adjusted for age, sex, diabetes, APOE ε4 carrier status and other potential confounders, including cardiovascular risk factors, and additionally stratified by sex and APOE ε4 status.ResultParticipants with higher EN‐RAGE and lower sRAGE levels were more likely to have dementia (adjusted odds ratio (OR); 3.64 [95% confidence interval 1.56‐8.50] and OR 0.39 [0.17‐0.83], for high level compared to low level). During follow‐up (median 12.4 years), 161 participants developed dementia, of whom 130 Alzheimer’s disease (AD). Higher EN‐RAGE was non‐significantly associated with higher risk of dementia during the first years of follow‐up (adjusted hazard ratio (HR); 1.48 [0.52‐4.25] after 4 years of follow‐up), while a lower risk was found over the entire follow‐up duration (HR 0.65 [0.42‐1.01]) (Figure 1). Higher SAF was associated with lower global cognitive function (adjusted difference in z score per SAF standard deviation (SD); 0.07 [0.04‐0.11]). This effect was stronger for carriers of the APOE ε4 allele (0.15 [0.07‐0.22]).ConclusionOur results indicate involvement of the AGE‐RAGE system in the pathophysiology of dementia, independent of the history of diabetes, showing involvement of EN‐RAGE and sRAGE, and of SAF in cognitive functioning. These associations were stronger for APOE ε4 carriers, suggesting a combined role of AGEs and APOE in neurodegeneration.

Soluble Receptor for Advanced Glycation End Products and Its Forms in COVID-19 Patients with and without Diabetes Mellitus: A Pilot Study on Their Role as Disease Biomarkers.

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.

Circulating soluble receptor for advanced glycation end products and other factors in type 2 diabetes patients with colorectal cancer

BackgroundRecent study showed that individuals with type 2 diabetes have a high risk of developing colorectal cancer (CRC), in which Receptor for Advanced Glycation End Products (RAGE) plays a pivotal role. We conducted a cross-sectional study to examine the relationships of circulating sRAGE, CRC and other clinical factors in type2 diabetes patients.MethodsA total of 150 type 2 diabetes patients aged 50 years and older were enrolled, including 50 patients with CRC and 100 patients without CRC. We measured Serum levels of sRAGE and interleukin-6(IL-6) using an enzyme-linked immunosorbent assay (ELISA). In addition, other clinical parameters were also measured during hospitalization.ResultsType 2 diabetes patients with CRC had higher triglyceride, total cholesterol, IL-6, and circulating sRAGE levels and lower use of medicines than type 2 diabetes patients without CRC. Circulating sRAGE was associated with an increased risk for CRC (OR = 2.289 for each SD increase in sRAGE, 95% CI = 1.037–5.051; P = 0.04) among Type 2 diabetes patients after adjustment for confounders. Furthermore, circulating sRAGE levels among type 2 diabetes patients were positively correlated with triglyceride (r = 0.377, P < 0.001), total cholesterol (r = 0.491, P < 0.001), and low-density lipoprotein cholesterol (LDL-c)(r = 0.330, P < 0.001) levels; the homeostatic model assessment for insulin resistance(HOMA-IR)score (r = 0.194, P = 0.017); and fasting serum insulin (r = 0.167, P = 0.041) and IL-6 (r = 0.311, P < 0.001) concentrations.ConclusionsOur results suggested that circulating sRAGE is independently risk factor for CRC, and also closely related to inflammation, dyslipidemia in type 2 diabetes patients.

Serum Soluble Receptor for Advanced Glycation End Products in Infants With Bronchiolitis: Associations With Acute Severity and Recurrent Wheeze.

Although bronchiolitis contributes to substantial acute (eg, intensive care use) and chronic (eg, recurrent wheeze) morbidities in young children, the pathobiology remains uncertain. We examined the associations of serum soluble receptor for advanced glycation end products (sRAGE) with acute and chronic morbidities of bronchiolitis including recurrent wheeze. A multicenter, multiyear, cohort study of infants hospitalized for bronchiolitis was analyzed. We measured the serum sRAGE level at hospitalization and its association with intensive care use (use of mechanical ventilation and/or admission to the intensive care unit) and development of recurrent wheeze by age 3 years. We performed causal mediation analysis to estimate indirect (mediation) and direct effects of sRAGE on recurrent wheeze. In 886 infants with bronchiolitis, the median age was 2.9 months. Overall, 15% underwent intensive care and 32% developed recurrent wheeze. In multivariable modeling adjusting for 11 confounders, a higher presenting sRAGE level was associated with lower risk of intensive care (odds ratio for each 1-log increment, 0.39; 95% confidence interval [CI], .16 -.91; P = .03) and significantly lower rate of recurrent wheeze (hazard ratio [HR], 0.58; 95% CI, .36 -.94; P = .03). In mediation analysis, the direct effect was significant (HR, 0.60; 95% CI, .37 -.97; P = .04), while the indirect effect was not (P = .30). Serum sRAGE levels were inversely associated with acute and chronic morbidities of bronchiolitis. The effect of sRAGE on development of recurrent wheeze is potentially driven through pathways other than acute severity of bronchiolitis.

Circulating Ligands of the Receptor for Advanced Glycation End Products and the Soluble Form of the Receptor Modulate Cardiovascular Cell Apoptosis in Diabetes.

We determined whether plasma concentrations of the receptor for advanced glycation end products (RAGE) and the soluble (s) form of RAGE (sRAGE) in healthy individuals and patients with type 2 diabetes (T2D) modulate vascular remodeling. Healthy individuals and patients with T2D were divided into two age groups: young = <35 years old or middle-aged (36–64 years old) and stratified based on normal glucose tolerance (NGT), impaired (IGT), and T2D. Plasma titers of sRAGE, the RAGE ligands, AGEs, S100B, S100A1, S100A6, and the apoptotic marker Fas ligand Fas(L) were measured by enzyme-linked immunosorbent assay (ELISA). The apoptotic potential of the above RAGE ligands and sRAGE were assessed in cultured adult rat aortic smooth muscle cells (ASMC). In NGT individuals, aging increased the circulating levels of AGEs and S100B and decreased sRAGE, S100A1 and S100A6. Middle-aged patients with T2D presented higher levels of circulating S100B, AGEs and FasL, but lower levels of sRAGE, S100A1 and S100A6 than individuals with NGT or IGT. Treatment of ASMC with either AGEs or S100B at concentrations detected in T2D patients increased markers of inflammation and apoptosis. Responses attenuated by concomitant administration of sRAGE. In middle-aged patients with T2D, lower circulating plasma levels of sRAGE may limit decoy and exogenous trapping of deleterious pro-apoptotic/pro-inflammatory RAGE ligands AGEs and S100B, increasing the risk for diabetic complications.

The Gly82Ser polymorphism in the receptor for advanced glycation end products is associated with increased risk for coronary events in the general population

Abstract Background/Introduction Activation of the receptor for advanced glycation end products (RAGE) by AGEs and various immune mediators has pro-inflammatory and pro-atherogenic effects. RAGE also exists in a soluble form, sRAGE, that acts as a decoy receptor for RAGE ligands. Low plasma sRAGE has previously been found to be associated with a higher risk for major adverse coronary events (MACE) in the population. Purpose The purpose of our study was to examine the causality of the association, by exploring whether genetic variants that influence sRAGE are associated with atherosclerosis progression and incident MACE and mortality in the population. Methods We performed a genome-wide association study (GWAS) in 4192 individuals from a randomly selected subgroup of a population-based cohort. Subsequently, we explored the associations between the identified single nucleotide polymorphims (SNPs) associated with plasma sRAGE levels, baseline intima media thickness (IMT) and IMT progression in the common carotid artery during a median follow-up of 16.5 years. Further, we analyzed the prospective relationships between the sRAGE-associated SNPs, incident MACE and mortality in the entire population-based cohort of 29245 individuals. The median follow-up time from baseline was 21.2 years for MACE and 21.6 years for total mortality (time to event or end of follow-up). Results We found the minor alleles of two single nucleotide polymorphisms (SNPs), rs2070600 and rs204993, to be independently associated with lower plasma sRAGE. While rs204993 is a silent intronic mutation, rs2070600 is known to cause a Gly82Ser polymorphism in the ligand binding domain, enhancing RAGE propensity for activation. In Cox regression analyses, we found an association between the minor T (vs. C) allele of rs2070600 and increased risk for first-time MACE [HR 1.12 (1.02–1.23); P=0.023]. The association was independent of traditional cardiovascular risk factors, blood pressure-lowering medication and lipid-lowering medication at baseline. rs204993 was not associated with MACE. Neither SNP was associated with carotid IMT at baseline or with IMT progression. We did not identify any relationships with total mortality. Conclusions We demonstrate for the first time an independent link between a genetic RAGE determinant and the risk for MACE in the population. Despite both identified SNPs being associated with lower sRAGE levels, only the functional rs2070600 mutation was associated with MACE, suggesting that the link is probably due to the enhancement of RAGE function rather than to the sRAGE lowering effect. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): This study was supported by grants from the Swedish Research Council and the Swedish Heart and Lung foundation.

Higher levels of the soluble receptor for advanced glycation end products and lower levels of the extracellular newly identified receptor for advanced glycation end products were associated with lipid-lowering drugs in patients with type 1 diabetes: a comparative cross-sectional study

BackgroundThe receptors for advanced glycation end products (RAGE) are increased in atherosclerotic plaques. Soluble (s)RAGE decreases, whereas the extracellular newly identified receptor for advanced glycation end products (EN-RAGE) increases inflammatory responses mediated by RAGE. The aims were to explore whether sRAGE, EN-RAGE and the EN-RAGE/sRAGE ratio, were associated with the use of lipid-lowering drugs (LLD) and/or antihypertensive drugs (AHD) in patients with type 1 diabetes (T1D).MethodsCross-sectional design. T1D patients were consecutively recruited from one diabetes clinic. Blood samples were collected, supplemented with data from electronic health records. sRAGE and EN-RAGE were analysed by enzyme linked immunosorbent assays. An EN-RAGE/sRAGE ratio was calculated. Adjustments were performed with inflammatory and metabolic variables, s-creatinine, depression, smoking, physical inactivity, medication, and cardiovascular complications. Multiple regression analyses were performed.ResultsIn this study 283 T1D patients (men 56%, 18–59 years) were included. One-hundred and thirty LLD users compared to 153 non-users had lower levels of the EN-RAGE/sRAGE ratio (P = 0.009), and 89 AHD users compared to 194 non-users had lower levels of sRAGE (P = 0.031). The use of LLD (inversely) (B coefficient − 0.158, P = 0.033) and the use of AHD (B coefficient 0.187, P = 0.023) were associated with the EN-RAGE/sRAGE ratio. sRAGE (Lg10) (per unit) (adjusted odds ratio (AOR) = 3.5, 95% CI = 1.4–9.1, P = 0.009), EN-RAGE (Lg10) (per unit) (inversely) (AOR 0.4, 95% CI = 0.2–1.0, P = 0.046), age (P < 0.001), and triglycerides (P < 0.029), were associated with LLD. sRAGE (Lg10) (per unit) (inversely) (AOR = 0.2, 95% CI = 0.1–0.5, P = 0.001), diabetes duration, triglycerides, s-creatinine, and systolic BP (all P values < 0.043), were associated with AHD.ConclusionsHigher sRAGE levels and lower EN-RAGE levels were linked to the use of LLD, whereas lower sRAGE levels were linked to the use of AHD. No other variables but the use of LLD and the use of AHD were linked to the EN-RAGE/sRAGE ratio. This may be of major importance as sRAGE is an inhibitor and EN-RAGE is a stimulator of inflammatory processes mediated by RAGE.

Relationship Between Peripheral Transport Proteins and Plasma Amyloid-β in Patients with Alzheimer's Disease Were Different from Cognitively Normal Controls: A Propensity Score Matching Analysis.

Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-β (Aβ). However, their relationship is seldom discussed, especially in Alzheimer's disease (AD). To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aβ were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aβ were analyzed using Pearson's correlation analysis followed by multiple linear regression separately in the original population and matched participants. After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aβ40 in matched CN controls (r = 0.222, p = 0.008) but not in patients with AD (r = 0.137, p = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aβ40 in the CN group (β= 7.347, p = 0.014) but not in the AD group (β= 10.409, p = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aβ42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aβ40 or Aβ42 in either group. The significant correlation between sLRP1 and plasma Aβ40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

In vivo quantitative analysis of advanced glycation end products in atopic dermatitis—Possible culprit for the comorbidities?

Advanced glycation end products (AGEs) interact with the membrane-bound receptor for AGEs (RAGE), consequently amplifying the inflammatory response. Soluble receptor for AGE (sRAGE) and endogenous secretory RAGE (esRAGE) act as decoys for AGE and competitively sequester RAGE ligands, thereby serving a cytoprotective role. Our objective was to investigate AGE expression and their receptors in the serum and skin of patients with atopic dermatitis (AD). In this case-control study, the levels of AGE, sRAGE and esRAGE were measured in the blood samples and corneocytes of 29 adult patients with AD and 12 healthy controls by ELISA. Corneocyte AGE levels increased in the AD group (P=.002). Higher corneocyte AGE levels were observed in the severe AD than in the milder form of AD. No significant difference in serum AGE level was observed in patients with AD and healthy controls. Serum sRAGE markedly decreased in patients with AD (P=.007) and serum esRAGE followed a similar trend. In conclusion, dermal accumulation of AGE in AD may have a role in fuelling skin inflammation. The potential after-effects of reduced neutralizer on systemic risk need further evaluation.

SRAGE as severe acute bronchiolitis biomarker, prospective observational study.

Acute bronchiolitis (AB) is the leading cause of hospitalization in infants and around 5% require intensive care treatment. Early identification of children diagnosed with AB ata high risk of severe progression is of great interest. The receptor for advanced glycation end products (RAGE), highly expressed in lung tissue, regulates immune responses and inflammation, and its soluble form, sRAGE, is believed to have an anti-inflammatory role. We hypothesized serum sRAGE might be a major determinant of AB severity and prognosis. This study was conducted to measure serum sRAGE in infants with severe AB and to assess its correlation with clinical severity, immediate complications, and outcome. Single-center, prospective, observational study of hospitalized children with severe bronchiolitis admitted to the Pediatric Intensive Care Unit (PICU), from September 2015 to September 2016. A total of 52 children and 27 controls were included. The cases age ranged from 11 days to 21 months, resulting in a significant age difference with controls (11.85 vs 4.84 months, P < .01). Serum levels of sRAGE were lower but not significant in severe AB patients than in controls (1350.93 vs 1450.42 pg/mL; P = .399). No correlation was found between serum sRAGE and causative viruses, clinical symptoms, Wood-Downes score (a clinical severity score) on admission, respiratory support, or length of hospital stay. Serum sRAGE was also lower in the cases having had a previous respiratory disease (1463.84 vs 1072.43 pg/mL; P = .049). However, it was higher in patients with any lung consolidation on the chest X-ray (1584.79 vs 1131.62 pg/mL; P = .044) and weakly positively correlated with classical biomarkers (maximum C-reactive protein, +0.295, P = .034; maximum procalcitonin, +0.309; P = .029). This single-center study reveals that sRAGE couldn't predict AB severity or outcome in children hospitalized at PICU. Nevertheless, it significantly increased in the presence of any lung consolidation and had a positive correlation with classical biomarkers. The utility of sRAGE in this population could be probably elucidated with a better understanding of AGE-RAGE axis.