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1.  sRAGE Induces Human Monocyte Survival and Differentiation 
The receptor for advanced glycation end products (RAGE) is produced either as a transmembrane or soluble form (sRAGE). Substantial evidence supports a role for RAGE and its ligands in disease. sRAGE is reported to be a competitive, negative regulator of membrane RAGE activation, inhibiting ligand binding. However, some reports indicate that sRAGE is associated with inflammatory disease. We sought to define the biological function of sRAGE on inflammatory cell recruitment, survival, and differentiation in vivo and in vitro. To test the in vivo impact of sRAGE, the recombinant protein was intratracheally administered to mice, which demonstrated monocyte- and neutrophil-mediated lung inflammation. We also observed that sRAGE induced human monocyte and neutrophil migration in vitro. Human monocytes treated with sRAGE produced proinflammatory cytokines and chemokines. Our data demonstrated that sRAGE directly bound human monocytes and monocyte-derived macrophages. Binding of sRAGE to monocytes promoted their survival and differentiation to macrophages. Furthermore, sRAGE binding to cells increased during maturation, which was similar in freshly isolated mouse monocytes compared with mature tissue macrophages. Because sRAGE activated cell survival and differentiation, we examined intracellular pathways that were activated by sRAGE. In primary human monocytes and macrophages, sRAGE treatment activated Akt, Erk, and NF-κB, and their activation appeared to be critical for cell survival and differentiation. Our data suggest a novel role for sRAGE in monocyte- and neutrophil-mediated inflammation and mononuclear phagocyte survival and differentiation.
PMCID: PMC3671884  PMID: 20574008
2.  RAGE inhibits human respiratory syncytial virus syncytium formation by interfering with F-protein function 
The Journal of General Virology  2013;94(Pt 8):1691-1700.
Human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infection. Infection is critically dependent on the RSV fusion (F) protein, which mediates fusion between the viral envelope and airway epithelial cells. The F protein is also expressed on infected cells and is responsible for fusion of infected cells with adjacent cells, resulting in the formation of multinucleate syncytia. The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that is constitutively highly expressed by type I alveolar epithelial cells. Here, we report that RAGE protected HEK cells from RSV-induced cell death and reduced viral titres in vitro. RAGE appeared to interact directly with the F protein, but, rather than inhibiting RSV entry into host cells, virus replication and budding, membrane-expressed RAGE or soluble RAGE blocked F-protein-mediated syncytium formation and sloughing. These data indicate that RAGE may contribute to protecting the lower airways from RSV by inhibiting the formation of syncytia, viral spread, epithelial damage and airway obstruction.
PMCID: PMC3749528  PMID: 23559480
3.  Blockade of RAGE suppresses periodontitis-associated bone loss in diabetic mice 
Journal of Clinical Investigation  2000;105(8):1117-1124.
Diabetes is associated with increased prevalence, severity, and progression of periodontal disease. To test the hypothesis that activation of RAGE (Receptor for Advanced Glycation End products) contributes to the pathogenesis of diabetes-associated periodontitis, we treated diabetic mice, infected with the human periodontal pathogen Porphyromonas gingivalis, with soluble RAGE (sRAGE). sRAGE is the extracellular domain of the receptor, which binds ligand and blocks interaction with, and activation of, cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss in a dose-dependent manner. Moreover, we noted decreased generation of the proinflammatory cytokines TNF-α and IL-6 in gingival tissue, as well as decreased levels of matrix metalloproteinases. Gingival AGEs were also reduced in mice treated with sRAGE, paralleling the observed suppression in alveolar bone loss. These findings link RAGE and exaggerated inflammatory responses to the pathogenesis of destructive periodontal disease in diabetes.
PMCID: PMC300834  PMID: 10772656
4.  Purification and Characterization of Mouse Soluble Receptor for Advanced Glycation End Products (sRAGE)* 
The Journal of biological chemistry  2004;279(48):50019-50024.
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface proteins that has been implicated as a progression factor in a number of pathologic conditions from chronic inflammation to cancer to Alzheimer’s disease. In such conditions, RAGE acts to facilitate pathogenic processes. Its secreted isoform, soluble RAGE or sRAGE, has the ability to prevent RAGE signaling by acting as a decoy. sRAGE has been used successfully in animal models of a range of diseases to antagonize RAGE-mediated pathologic processes. In humans, sRAGE results from alternative splicing of RAGE mRNA. This study was aimed to determine whether the same holds true for mouse sRAGE and, in addition, to biochemically characterize mouse sRAGE. The biochemical characteristics examined include glycosylation and disulfide patterns. In addition, sRAGE was found to bind heparin, which may mediate its distribution in the extracellular matrix and cell surfaces of tissues. Finally, our data indicated that sRAGE in the mouse is likely produced by carboxyl-terminal truncation, in contrast to the alternative splicing mechanism reported in humans.
PMCID: PMC1868562  PMID: 15381690
5.  Association of Four Genetic Polymorphisms of AGER and Its Circulating Forms with Coronary Artery Disease: A Meta-Analysis 
PLoS ONE  2013;8(7):e70834.
Considerable efforts have been devoted to evaluating the association of the receptor for advanced glycation end-products (gene AGER and protein: RAGE) genetic variants to coronary artery disease (CAD); the results, however, are often irreproducible. To generate more information, we sought to explore four common polymorphisms of AGER and its circulating forms associated with the risk of CAD via a meta-analysis.
Methodology/Principal Findings
Articles were identified by searching PubMed, EMBASE, Wanfang and CNKI databases before March 2013. Qualified articles had case-control designs and investigated AGER four polymorphisms (T-429C, T-374A, Gly82Ser, G1704A) or circulating soluble RAGE (sRAGE) or endogenous secretory RAGE (esRAGE) levels associated with CAD. Twenty-seven articles involving 39 independent groups fulfilled the predefined criteria. Overall, no significance was observed for all examined polymorphisms under allelic and dominant models. When restricting groups to CAD patients with diabetes mellitus or renal disease, deviations of risk estimates from the unity were stronger than overall estimates for all polymorphisms except for G1704A due to limited available studies. For example, under dominant model, having -429C allele increased the odds of developing CAD in diabetic patients by 1.22-fold (95% confidence interval (95% CI) 0.99–1.51; P = 0.06; I2 = 6.7%) compared with that of overall estimate of 1.15-fold (95% CI: 0.97–1.36; P = 0.111; I2 = 18.0%). Circulating sRAGE levels were non-significantly lower in CAD patients than in controls, whereas this reduction was totally and significantly reversed in CAD patients with diabetes mellitus (weighted mean difference: 185.71 pg/ml; 95% CI: 106.82 to 264.61 pg/ml). Circulating esRAGE levels were remarkably lower in CAD patients, as well as in subgroups with or without diabetes mellitus and without renal disease.
Our findings demonstrated that association of AGER genetic polymorphisms with CAD was potentiated in patients with diabetes mellitus or renal disease. Practically, circulating esRAGE might be a powerful negative predictor for the development of CAD.
PMCID: PMC3722145  PMID: 23894685
6.  Clinical chorioamnionitis is characterized by increased expression of the alarmin HMGB1 and One of Its Receptors, sRAGE 
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 is 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 the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). The objective of this study was to determine: 1) if clinical chorioamnionitis at term is associated with changes in amniotic fluid concentrations of HMGB1, sRAGE and esRAGE; and 2) if the amniotic fluid concentration of HMGB1 changes with labor or as a function of gestational age.
Amniotic fluid samples were collected from the following groups: 1) mid-trimester (MT) (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.
1) the median amniotic fluid HMGB1 concentration was higher in patients at term with clinical chorioamnionitis than that of 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).
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.
PMCID: PMC3914307  PMID: 22578261
danger signal; intra-amniotic inflammation; sterile inflammation; pregnancy; neuroinflammation; neuro-immune reflects; amniotic fluid; DAMPs; damage-associated molecular patterns; intra-amniotic infection; term labor
7.  sRAGE and Risk of Diabetes, Cardiovascular Disease, and Death 
Diabetes  2013;62(6):2116-2121.
Advanced glycation end products (AGEs) and their receptors are strongly implicated in the development of diabetes complications. When stimulated by AGEs, the receptors for AGEs (RAGEs) induce inflammation and are thought to fuel disease progression. Soluble circulating RAGE (sRAGE) may counteract the detrimental effects of RAGE. We measured sRAGE in stored plasma from a random sample of 1,201 participants in the Atherosclerosis Risk in Communities (ARIC) Study who were aged 47–68 years, had normal kidney function, and had no history of cardiovascular disease. In cross-sectional analyses, black race, male sex, higher BMI, and higher C-reactive protein were independently associated with low sRAGE. The racial difference was striking, with blacks approximately three times more likely to have low sRAGE compared with whites even after adjustment. During ~18 years of follow-up, there were 192 incident coronary heart disease events, 53 ischemic strokes, 213 deaths, and 253 cases of diabetes (among the 1,057 persons without diabetes at baseline). In multivariable Cox models comparing risk in the first quartile with that in the fourth quartile of baseline sRAGE, low levels of sRAGE were significantly associated with risk of diabetes (hazard ratio 1.64 [95% CI 1.10–2.44]), coronary heart disease (1.82 [1.17–2.84]), and mortality (1.72 [1.11–2.64]) but not ischemic stroke (0.78 [0.34–1.79]). In conclusion, we found that low levels of sRAGE were a marker of future chronic disease risk and mortality in the community and may represent an inflammatory state. Racial differences in sRAGE deserve further examination.
PMCID: PMC3661610  PMID: 23396398
8.  Association between Preoperative Plasma sRAGE Levels and Recovery from Cardiac Surgery 
Mediators of Inflammation  2013;2013:496031.
Background. The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating receptor, and soluble RAGE (sRAGE) is a marker of cellular RAGE expression. This study investigated whether raised plasma levels prior to surgery of sRAGE or S100A8/A9 (a RAGE ligand) were associated with longer duration of hospital care in patients undergoing cardiac surgery necessitating cardiopulmonary bypass. Methods. Patients (n = 130) undergoing elective cardiac surgery were enrolled prospectively. Plasma sRAGE and S100A8/A9 concentrations were measured before and 2 h after surgery. Results. Preoperative plasma sRAGE increased significantly (P < 0.0001) from 1.06 ng/mL (IQR, 0.72–1.76) to 1.93 ng/mL (IQR, 1.14–2.63) 2 h postoperatively. Plasma S100A8/9 was also significantly (P < 0.0001) higher 2 h postoperatively (2.37 μg/mL, IQR, 1.81–3.05) compared to pre-operative levels (0.41 μg/mL, IQR, 0.2–0.65). Preoperative sRAGE, but not S100A8/A9, was positively and significantly correlated with duration of critical illness (r = 0.3, P = 0.0007) and length of hospital stay (LOS; r = 0.31, P < 0.0005). Multivariate binary logistic regression showed preoperative sRAGE to be, statistically, an independent predictor of greater than median duration of critical illness (odds ratio 16.6, P = 0.014) and to be, statistically, the strongest independent predictor of hospital LOS. Conclusion. Higher preoperative plasma sRAGE levels were associated with prolonged duration of care in adults undergoing cardiac surgery requiring cardiopulmonary bypass.
PMCID: PMC3780651  PMID: 24089588
9.  Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study 
Respiratory Research  2011;12(1):37.
The receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor that can initiate and perpetuate inflammation. Its soluble isoform (sRAGE) acts as a decoy receptor for RAGE ligands, and is thought to afford protection against inflammation. With the present study, we aimed at determining whether circulating sRAGE is correlated with emphysema and chronic cor pulmonale in chronic obstructive pulmonary disease (COPD).
In 200 COPD patients and 201 age- and sex-matched controls, we measured lung function by spirometry, and sRAGE by ELISA method. We also measured the plasma levels of two RAGE ligands, N-epsilon-carboxymethyl lysine and S100A12, by ELISA method. In the COPD patients, we assessed the prevalence and severity of emphysema by computed tomography (CT), and the prevalence of chronic cor pulmonale by echocardiography. Multiple quantile regression was used to assess the effects of emphysema, chronic cor pulmonale, smoking history, and comorbid conditions on the three quartiles of sRAGE.
sRAGE was significantly lower (p = 0.007) in COPD patients (median 652 pg/mL, interquartile range 484 to 1076 pg/mL) than in controls (median 869 pg/mL, interquartile range 601 to 1240 pg/mL), and was correlated with the severity of emphysema (p < 0.001), the lower the level of sRAGE the greater the degree of emphysema on CT. The relationship remained statistically significant after adjusting for smoking history and comorbid conditions. In addition, sRAGE was significantly lower in COPD patients with chronic cor pulmonale than in those without (p = 0.002). Such difference remained statistically significant after adjusting for smoking history, comorbidities, and emphysema severity. There was no significant difference in the plasma levels of the two RAGE ligands between cases and controls.
sRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without airflow obstruction. Emphysema and chronic cor pulmonale are independent predictors of reduced sRAGE in COPD.
PMCID: PMC3072955  PMID: 21450080
10.  Association of plasma sRAGE, but not esRAGE with lung function impairment in COPD 
Respiratory Research  2014;15(1):24.
Plasma soluble Receptor for Advanced Glycation End Product (sRAGE) is considered as a biomarker in COPD. The contribution of endogenous sRAGE (esRAGE) to the pool of plasma sRAGE and the implication of both markers in COPD pathogenesis is however not clear yet. The aim of the current study was therefore to measure plasma levels of esRAGE comparative to total sRAGE in patients with COPD and a control group. Further, we established the relations of esRAGE and total sRAGE with disease specific characteristics such as lung function and DLCO, and with different circulating AGEs.
Plasma levels of esRAGE and sRAGE were measured in an 88 patients with COPD and in 55 healthy controls. FEV1 (%predicted) and FEV1/VC (%) were measured in both groups; DLCO (%predicted) was measured in patients only. In this study population we previously reported that the AGE Nϵ-(carboxymethyl) lysine (CML) was decreased, Nϵ-(carboxyethyl) lysine (CEL) increased and pentosidine was not different in plasma of COPD patients compared to controls.
Plasma esRAGE (COPD: 533.9 ± 412.4, Controls: 848.7 ± 690.3 pg/ml; p = 0.000) was decreased in COPD compared to controls. No significant correlations were observed between plasma esRAGE levels and lung function parameters or plasma AGEs. A positive correlation was present between esRAGE and total sRAGE levels in the circulation. Confirming previous findings, total sRAGE (COPD: 512.6 ± 403.8, Controls: 1834 ± 804.2 pg/ml; p < 0.001) was lower in patients compared to controls and was positively correlated FEV1 (r = 0.235, p = 0.032), FEV1/VC (r = 0.218, p = 0.047), and DLCO (r = 0.308, p = 0.006). sRAGE furthermore did show a significant positive association with CML (r = 0.321, p = 0.003).
Although plasma esRAGE is decreased in COPD patients compared to controls, only total sRAGE showed a significant and independent association with FEV1, FEV1/VC and DLCO, indicating that total sRAGE but not esRAGE may serve as marker of COPD disease state and severity.
PMCID: PMC3944004  PMID: 24564838
11.  Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats 
Objective: Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney. Methods: Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Results: Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased. Conclusions: Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.
PMCID: PMC3150719  PMID: 21796806
Receptor for advanced glycation end-product (RAGE); Endogenous secretory RAGE (esRAGE); Soluble RAGE (sRAGE); Diabetic nephropathy; Atorvastatin
12.  Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients 
Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress – all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis.
To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI.
Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients.
sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients.
Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.
PMCID: PMC2903037  PMID: 22477551
Advanced glycation end product; Non-ST elevation myocardial infarction; Soluble receptor for advanced glycation end products; Soluble vascular cell adhesion molecule-1; Tumor necrosis factor-alpha
13.  Soluble receptor for advanced glycation end products and risk of liver cancer 
Hepatology (Baltimore, Md.)  2013;57(6):2338-2345.
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 AGEs/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 (HCC) in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample in 1985–1988. 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 cases and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available on most cases and 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 (sRAGE: RR, highest versus lowest tertile, 0.77; 95% CI, 0.48–1.24; Ptrend=0.28; continuous RR, 0.86; 95% CI, 0.75–0.99; CML-AGE: RR, highest versus lowest tertile, 0.19; 95% CI, 0.10–0.35; Ptrend <0.0001; continuous RR, 0.74; 95% CI, 0.65–0.84). Further adjustment for glucose and insulin, or exclusion of cases 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 non-smokers.
PMCID: PMC3644530  PMID: 23325627
sRAGE; CML-AGE; case-cohort; incidence; men
14.  Higher serum soluble receptor for advanced glycation end product levels and lower prevalence of metabolic syndrome among Japanese adult men: a cross-sectional study 
Although several studies showed that decreased soluble receptor for advanced glycation end products (sRAGE) is associated with metabolic syndrome (MetS), inflammation level has not been considered, even though ligand–RAGE interaction induces inflammation. The objective of the study was to determine the association between sRAGE and MetS among Japanese adult in a cross-sectional survey, taking the level of low grade inflammation into consideration.
Serum soluble RAGE (sRAGE) were measured in 712 men and 176 women aged 30–83 years with serum C-reactive protein (hsCRP) concentration below 3 mg/L. MetS was defined using the criteria of the American Heart Association Scientific Statements of 2009.
After multivariable adjustment, among men, higher sRAGE levels were associated with lower odds of MetS as well as central obesity and elevated blood pressure. Comparing the extreme tertiles of sRAGE, odds ratios (95% confidence interval) were 0.58 (0.36–0.95; P for trend = 0.001) for MetS; 0.41 (0.25–0.52; P for trend < 0.001) for central obesity; and 0.45 (0.29–0.70; P for trend < 0.001) for elevated blood pressure. Moreover, participants were categorized according to their median hsCRP and sRAGE values. Men in the higher hsCRP/higher sRAGE category had a 40% lower odds ratio for MetS than those in the higher hsCRP/lower sRAGE category (P = 0.031). Among women, there was no association between sRAGE levels and the prevalence of MetS.
Higher circulating RAGE concentrations were associated with lower prevalence of MetS and its components among Japanese men.
PMCID: PMC4016590  PMID: 24602408
Endogenous secretory RAGE; Low grade inflammation; CRP
15.  Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis 
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptor molecules. High concentrations of three of its putative proinflammatory ligands, S100A8/A9 complex (calprotectin), S100A8, and S100A12, are found in rheumatoid arthritis (RA) serum and synovial fluid. In contrast, soluble RAGE (sRAGE) may prevent proinflammatory effects by acting as a decoy. This study evaluated the serum levels of S100A9, S100A8, S100A12 and sRAGE in RA patients, to determine their relationship to inflammation and joint and vascular damage.
Serum sRAGE, S100A9, S100A8 and S100A12 levels from 138 patients with established RA and 44 healthy controls were measured by ELISA and compared by unpaired t test. In RA patients, associations with disease activity and severity variables were analyzed by simple and multiple linear regressions.
Serum S100A9, S100A8 and S100A12 levels were correlated in RA patients. S100A9 levels were associated with body mass index (BMI), and with serum levels of S100A8 and S100A12. S100A8 levels were associated with serum levels of S100A9, presence of anti-citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF). S100A12 levels were associated with presence of ACPA, history of diabetes, and serum S100A9 levels. sRAGE levels were negatively associated with serum levels of C-reactive protein (CRP) and high-density lipoprotein (HDL), history of vasculitis, and the presence of the RAGE 82Ser polymorphism.
sRAGE and S100 proteins were associated not just with RA inflammation and autoantibody production, but also with classical vascular risk factors for end-organ damage. Consistent with its role as a RAGE decoy molecule, sRAGE had the opposite effects to S100 proteins in that S100 proteins were associated with autoantibodies and vascular risk, whereas sRAGE was associated with protection against joint and vascular damage. These data suggest that RAGE activity influences co-development of joint and vascular disease in rheumatoid arthritis patients.
PMCID: PMC2688185  PMID: 19284577
16.  Soluble receptor for advanced glycation end-products and progression of airway disease 
The receptor for advanced glycation end-products (RAGE) is highly expressed in the lung, where it is believed to have a homeostatic role. Reduced plasma levels of soluble RAGE (sRAGE) have been reported in patients with chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the association of plasma sRAGE levels with a longitudinal decline of lung function. We have also measured plasma levels of high mobility group box 1 (HMGB1), a RAGE ligand which has been associated with chronic inflammatory diseases including COPD.
Baseline plasma concentrations of sRAGE and HMGB1 were measured in non-smokers (n = 32), smokers without COPD (n = 212), and smokers with COPD (n = 51), and the associations of the plasma sRAGE and HMGB1 levels with longitudinal declines of lung function during a 4-year follow-up period were analysed.
The plasma levels of sRAGE were significantly lower in smokers without COPD and in smokers with COPD, as compared to those of non-smokers. Plasma sRAGE levels positively correlated with FVC and FEV1 and inversely correlated with BMI and pack-years. Lower sRAGE levels were associated with greater declines of FEV1/FVC over 4 years in all participants. Moreover, multivariate regression analysis indicated that the baseline plasma sRAGE concentration was an independent predictor of FEV1/FVC decline in all groups. A subgroup analysis showed that decreased sRAGE levels are significantly associated with a more rapid decline of FEV1/FVC in smokers with COPD. There was no significant correlation between plasma HMGB1 levels and longitudinal decline of lung function.
Lower plasma concentrations of sRAGE were associated with greater progression of airflow limitations over time, especially in smokers with COPD, suggesting that RAGE might have a protective role in the lung.
PMCID: PMC4021457  PMID: 24758342
17.  Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control 
Arthritis Research & Therapy  2005;7(4):R817-R824.
The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily being expressed as a cell surface molecule and binding a variety of ligands. One of these ligands is high-mobility group box chromosomal protein 1, a potent proinflammatory cytokine, expression of which is increased in synovial tissue and in synovial fluid of rheumatoid arthritis (RA) patients. The interaction of high-mobility group box chromosomal protein 1 with cell-surface RAGE leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) may abrogate cellular activation since the ligand is bound prior to interaction with the surface receptor.
Our aim was to analyse to what extent sRAGE is present in patients with chronic joint inflammation (RA) as compared with patients with non-inflammatory joint disease and with healthy subjects, and to assess whether there is an association between sRAGE levels and disease characteristics.
Matching samples of blood and synovial fluid were collected from 62 patients with RA with acute joint effusion. Blood from 45 healthy individuals, synovial fluid samples from 33 patients with non-inflammatory joint diseases and blood from six patients with non-inflammatory joint diseases were used for comparison. sRAGE levels were analysed using an ELISA.
RA patients displayed significantly decreased blood levels of sRAGE (871 ± 66 pg/ml, P < 0.0001) as compared with healthy controls (1290 ± 78 pg/ml) and with patients with non-inflammatory joint disease (1569 ± 168 pg/ml). Importantly, sRAGE levels in the synovial fluid of RA patients (379 ± 36 pg/ml) were lower than in corresponding blood samples and correlated significantly with blood sRAGE. Interestingly, a significantly higher sRAGE level was found in synovial fluid of RA patients treated with methotrexate as compared with patients without disease-modifying anti-rheumatic treatment.
We conclude that a decreased level of sRAGE in patients with RA might increase the propensity towards inflammation, whereas treatment with methotrexate counteracts this feature.
PMCID: PMC1175032  PMID: 15987483
18.  Influence of Physical Activity Intervention on Circulating Soluble Receptor for Advanced Glycation end Products in Elderly Subjects 
Inflammation, often accompanied by oxidation, caused by advanced glycation end products (AGEs) may be quenched by the soluble receptor for AGEs (sRAGE). The present study aimed to investigate the influence of physical activity on circulating sRAGE, and the association between changes of circulating sRAGE and paraoxonase1 (PON1) activity (as an antioxidative enzyme) in a physical activity intervention study on an elderly subject cohort.
Serum sRAGE, PON1 activity and cardiometabolic variables were measured in 30 community-dwelling asymptomatic Japanese volunteers (15 men/15 women, mean age 65 years) in the pre- and post-phase of a 6-month interventional program designed to increase physical activity.
The body mass index and sRAGE levels (1103 ± 496 to 1030 ± 437 ng/L, P < 0.05) were significantly reduced during the intervention period. In addition, the change of sRAGE was significantly and inversely correlated with that of PON1 activity, independent of the other cardiometabolic variables (β = - 0.511, P < 0.01).
This study showed a reduction of sRAGE levels, and an inverse correlation between sRAGE and PON1 activity, after the intervention study increasing physical activity on an elderly population. These findings represent a modest but significant modulation of sRAGE by this type of exercise intervention, which warranted future studies on the clinical relevance of sRAGE changes in physical activity.
AGEs; RAGE; Paraoxonase1; Exercise; Atherosclerosis
PMCID: PMC3279487  PMID: 22383913
19.  Participation of the Receptor for Advanced Glycation End-products in Efferocytosis 
Clearance of apoptotic cells by macrophages and other phagocytic cells, called efferocytosis, is a central process in the resolution of inflammation. Although the receptor for advanced glycation end products (RAGE) has been shown to participate in a variety of acute and chronic inflammatory processes in the lungs and other organs, a role for RAGE in efferocytosis has not been reported. In the present studies, we examined the potential involvement of RAGE in efferocytosis. Macrophages from transgenic RAGE−/− mice showed a decreased ability to engulf apoptotic neutrophils and thymocytes. Pretreatment of RAGE+/+ macrophages with advanced glycation end products, which competitively bind to RAGE, or Abs against RAGE diminished phagocytosis of apoptotic cells. Overexpression of RAGE in human embryonic kidney 293 cells resulted in an increased ability to engulf apoptotic cells. Furthermore, we found that incubation with soluble RAGE enhances phagocytosis of apoptotic cells by both RAGE+/+ and RAGE−/− macrophages. Direct binding of RAGE to phosphatidylserine (PS), an “eat me” signal highly expressed on apoptotic cells, was shown by using solid-phase ELISA. The ability of RAGE to bind to PS on apoptotic cells was confirmed in an adhesion assay. Decreased uptake of apoptotic neutrophils by macrophages was found under in vivo conditions in the lungs and peritoneal cavity of RAGE−/− mice. These results demonstrate a novel role for RAGE in which it is able to enhance efferocytosis through binding to PS on apoptotic cells.
PMCID: PMC3955180  PMID: 21502377
20.  Evidence that Serum Levels of the Soluble Receptor for Advanced Glycation End-Products are Inversely Associated with Pancreatic Cancer Risk: a Prospective Study 
Cancer research  2011;71(10):3582-3589.
Cigarette smoking, obesity, type 2 diabetes, and to a less extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end-products (AGEs). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of Nε-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case-cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985-1988). We measured CML-AGE, sRAGE, glucose and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% confidence intervals (CI), adjusted for age, years of smoking and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer (fifth compared with first quintile, RR (95% CI): 0.68 (0.38-1.22), Ptrend = 0.27). In contrast, sRAGE levels were inversely associated with pancreatic cancer (fifth compared with first quintile, RR (95% CI): 0.46 (0.23-0.73), Ptrend = 0.002). Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers.
PMCID: PMC3096705  PMID: 21540233
advanced glycation end-products; soluble receptor for advanced glycation end-products; pancreatic cancer; risk; prospective
21.  Advanced Glycation End-Products, Soluble Receptor for Advanced Glycation End-Products and Risk of Colorectal Cancer 
Advanced glycation end-products (AGEs) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE/ligand engagement.
We examined the association between Nε-(carboxymethyl)lysine (CML), a prominent AGEs, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer five years after baseline (1985–1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% confidence intervals (CI).
Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI: 0.39, 1.07; P value for trend = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR: 0.52; 95% CI: 0.30, 0.89; P value for trend = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR: 1.20; 95% CI: 0.64, 2.26).
Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers.
This is the first epidemiologic study to implicate the receptor for advanced glycation end-products in colorectal cancer development.
PMCID: PMC3132292  PMID: 21527578
advanced glycation end-products; soluble receptor for advanced glycation end-products; colorectal cancer; risk; case-cohort; inflammation
22.  Plasma soluble receptor for advanced glycation end-products and risk of colorectal adenoma 
Receptor for advanced glycation end products (RAGE) plays an important role in promoting chronic inflammation with activation of NF-κB. Soluble form of RAGE (sRAGE) represents a naturally occurring competitive inhibitor of RAGE-mediated events. In a colonoscopy-based case-control study, we examined the associations of plasma levels of sRAGE, sTNF-αRI, sTNF-αRII, sIL-6R, EGF, IFNα2, G-CSF, MCP1, TNFβ, and VEGF with risk of colorectal adenoma. We prospectively identified 158 cases with colorectal adenoma and 203 polyp-free controls who were frequency-matched according to age, sex, race, and time of blood draw. Exposure information was collected using a questionnaire and fasting plasma samples were obtained before the colonoscopy. We used Luminex bead-based multiplex assays to determine level of biomarkers. Multivariate logistic regression model was used to estimate odds ratio (OR) and its 95% confidence interval (CI). Cases had insignificant lower levels of sRAGE, and higher levels of EGF and VEGF than controls. When the highest compared with the lowest category, the OR (95% CI) of colorectal adenoma was 0.55 (0.31-0.96) (P trend = 0.03) for sRAGE and 1.75 (1.05-2.93) (P trend =0.04) for VEGF, adjusting for age, smoking status, hypertension and type 2 diabetes. The inverse association between sRAGE and colorectal adenoma was seen only among those without hypertension (P interaction = 0.02). An inverse association between sRAGE and colorectal adenoma was in line with an inverse association between sRAGE and colorectal cancer previously reported. This study supported the involvement of RAGE-NF-kB related inflammatory mechanism in the formation of colorectal adenoma.
PMCID: PMC3508542  PMID: 23205181
Case-control; colorectal adenoma; risk; inflammation; sRAGE; VEGF; NF-kB
23.  Serum Levels of Receptors for Advanced Glycation End Products in Normal-Weight and Obese Children Born Small and Large for Gestational Age 
Diabetes Care  2012;35(6):1361-1363.
To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors.
We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR.
sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE.
sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE.
PMCID: PMC3357256  PMID: 22511256
24.  RAGE Modulates Hypoxia/Reoxygenation Injury in Adult Murine Cardiomyocytes via JNK and GSK-3β Signaling Pathways 
PLoS ONE  2010;5(4):e10092.
Advanced glycation end-products (AGEs) have been implicated in diverse pathological settings including diabetes, inflammation and acute ischemia/reperfusion injury in the heart. AGEs interact with the receptor for AGEs (RAGE) and transduce signals through activation of MAPKs and proapoptotic pathways. In the current study, adult cardiomyocytes were studied in an in vitro ischemia/reperfusion (I/R) injury model to delineate the molecular mechanisms underlying RAGE-mediated injury due to hypoxia/reoxygenation (H/R).
Methodology/Principal Findings
Cardiomyocytes isolated from adult wild-type (WT), homozygous RAGE-null (RKO), and WT mice treated with soluble RAGE (sRAGE) were subjected to hypoxia for 30 minutes alone or followed by reoxygenation for 1 hour. In specific experiments, RAGE ligand carboxymethyllysine (CML)-AGE (termed “CML” in this manuscript) was evaluated in vitro. LDH, a marker of cellular injury, was assayed in the supernatant in the presence or absence of signaling inhibitor-treated cardiomyocytes. Cardiomyocyte levels of heterogeneous AGEs were measured using ELISA. A pronounced increase in RAGE expression along with AGEs was observed in H/R vs. normoxia in WT cardiomyocytes. WT cardiomyocytes after H/R displayed increased LDH release compared to RKO or sRAGE-treated cardiomyocytes. Our results revealed significant increases in phospho-JNK in WT cardiomyocytes after H/R. In contrast, neither RKO nor sRAGE-treated cardiomyocytes exhibited increased phosphorylation of JNK after H/R stress. The impact of RAGE deletion on GSK-3β phosphorylation in the cardiomyocytes subjected to H/R revealed significantly higher levels of phospho-GSK-3β/total GSK-3β in RKO, as well as in sRAGE-treated cardiomyocytes versus WT cardiomyocytes after H/R. Further investigation established a key role for Akt, which functions upstream of GSK-3β, in modulating H/R injury in adult cardiomyocytes.
These data illustrate key roles for RAGE-ligand interaction in the pathogenesis of cardiomyocyte injury induced by hypoxia/reoxygenation and indicate that the effects of RAGE are mediated by JNK activation and dephosphorylation of GSK-3β. The outcome in this study lends further support to the potential use of RAGE blockade as an adjunctive therapy for protection of the ischemic heart.
PMCID: PMC2852407  PMID: 20404919
25.  Clearance Kinetics and Matrix Binding Partners of the Receptor for Advanced Glycation End Products 
PLoS ONE  2014;9(3):e88259.
Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE). Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin.
PMCID: PMC3958346  PMID: 24642901

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