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

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

Racial differences in circulating levels of the soluble receptor for advanced glycation endproducts in middle-aged and older adults

BackgroundLow levels of the soluble receptor for advanced glycation endproducts (sRAGE) have been implicated in a number of chronic diseases. Previous studies indicate that sRAGE levels are ~ 30% lower in Blacks compared to Whites. However, the reasons for these differences are unclear.PurposeWe aimed to identify predictors of circulating sRAGE biomarkers among Black and White adults at high cardiac risk.MethodsSerum levels of total sRAGE, endogenous secretory RAGE (esRAGE), carboxymethyl-lysine (CML, a major RAGE ligand), and their ratios were measured in 99 Blacks and 454 Whites.ResultsBlacks had a more adverse cardiovascular risk profile, as well as lower median levels of total sRAGE (972 vs. 1564 pg/ml) and esRAGE (474 vs. 710 pg/ml) compared to Whites (p < 0.0001). In addition, the proportion of esRAGE was higher in Blacks (47% vs. 44%, p = 0.02), as were the CML/total sRAGE (0.89 vs. 0.56 ng/pg) and CML/esRAGE (1.72 vs. 1.20 ng/pg) ratios (p < 0.0001). Racial differences persisted after adjustment for key covariates including age, gender, tobacco use, comorbidities, BMI, blood pressure, glucose, insulin, triglycerides, C-reactive protein, and renal function (p < 0.05). Race alone accounted for nearly half of the variability in total sRAGE levels (10.6%; model explained 23.9%). In stratified analyses, gender and heart rate were independently associated with total sRAGE and esRAGE in Whites, while CML and C-reactive protein were associated with total sRAGE in Blacks.ConclusionsWe identified several independent predictors of sRAGE biomarkers. Notably, Black race was associated with an adverse AGE/RAGE profile, including lower sRAGE and higher CML/sRAGE ratios.     

Diabetes and advanced glycation endproducts

Bio-reactive advanced glycation endproducts (AGE) alter the structure and function of molecules in biological systems and increase oxidative stress. These adverse effects of both exogenous and endogenously derived AGE have been implicated in the pathogenesis of diabetic complications and changes associated with ageing including atherosclerosis, renal, eye and neurological disease. Specific AGE receptors and nonreceptor mechanisms contribute to these processes but also assist in the removal and degradation of AGE. The final disposal of AGE depends on renal clearance. Promising pharmacologic strategies to prevent AGE formation, reduce AGE toxicity, and/or inactivate AGE are under investigation.     

CD36, serves as a receptor for advanced glycation endproducts (AGE)

Interaction of advanced glycation endproducts (AGE) with AGE receptors induces several cellular phenomena relating potentially to diabetic complications. Five AGE receptors identified so far are receptor for AGE (RAGE), 80 K-H, OST-48, galectin-3, and macrophage scavenger receptor, types I and II (SR-A) [Eur. J. Biochem. 230 (1995) 408; Nature 386 (1997) 292.]. Since SR-A is known to belong to the class A scavenger receptor family and the scavenger receptor collectively represents a family of multiligand lipoprotein receptors, it is possible that CD36 belonging to class B scavenger receptor family (SR-B) can recognize AGE proteins as a ligand. This was tested in the present study at the cellular level by using Chinese hamster ovary (CHO) cells overexpressing human CD36 (CHO-CD36 cells). 125I-AGE-bovine serum albumin (BSA) was endocytosed in a dose-dependent fashion and underwent lysosomal degradation by CHO-CD36, but not wild-type CHO cells. Endocytic uptake of 125I-AGE-BSA by these cells was inhibited 50% by oxidized low-density lipoprotein (Ox-LDL) and 60% by FA6-152, an anti-CD36 antibody inhibiting cellular binding of Ox-LDL. Our results indicate that CD36 expressed by these cells mediates endocytic uptake and subsequent intracellular degradation of AGE proteins. Since CD36 is one of the major Ox-LDL receptors and is up-regulated in macrophage- and smooth muscle cell-derived foam cells in human atherosclerotic lesions, the present results suggest that, like Ox-LDL, AGE proteins generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications.     

Serum levels of soluble receptor for advanced glycation endproducts (sRAGE) are higher in ulcerative colitis and correlate with disease activity

Interaction of the receptor for advanced glycation endproducts (RAGE) with its ligands results in expression of inflammatory mediators, activation of NF-κB, and induction of oxidative stress, all of which have been implicated in the pathogenesis of inflammatory bowel diseases (IBD). Soluble receptor for advanced glycation endproducts (sRAGE) has recently emerged as a reliable biomarker of inflammation in numerous RAGE-mediated disorders.

Objective

To assess sRAGE levels in adult patients with IBD.

Method

Serum was collected from adult patients with Crohn's disease (CD, 56 patients), ulcerative colitis (UC, 60 patients), and healthy controls (HC, 113 subjects). Levels of sRAGE were determined by enzyme-linked immunosorbent assay.

Results

Serum sRAGE levels were elevated in IBD compared to HC and were higher in UC patients compared to CD and HC. Levels of sRAGE were significantly higher in the serum of UC patients with active disease compared to patients with inactive disease, but no association with the Montreal Classification was evident. Serum sRAGE was lower in CD patients with biological therapies.

Conclusions

These findings suggest that serum levels of sRAGE are altered in patients with intestinal inflammation and may reflect distinct immunoinflammatory pathogenesis of UC and CD.     

Role of advanced glycation endproducts in adynamic bone disease

To clarify the role of AGEs in adynamic bone disease, we investigated the effect of these substances on cultured human osteoblasts and parathyroid cells. AGEs-BSA significantly inhibited parathyroid hormone secretion in response to the low calcium concentration. In HEK-293 cells, expressing calcium-sensing receptors, the same AGE concentration caused a significant potentiation of the extracellular Ca(2+) induced-intracellular calcium concentration. AGEs significantly inhibited the synthesis of type I collagen and osteocalcin in response to stimulation with 1,25(OH)(2)D(3). These data suggest that AGEs are involved in the pathogenesis of adynamic bone disease by inhibiting PTH secretion in response to hypocalcemia and by inhibiting osteoblastic activity.     

Endogenous secretory receptor for advanced glycation end products in non-small cell lung carcinoma

RATIONALE: The receptor for advanced glycation end products is a multiligand receptor that plays an important role in regulating the invasiveness and metastatic potential of cancer cells. A recently discovered novel splice variant, the endogenous secretory receptor for advanced glycation end products, mediates the receptor for advanced glycation end-product-associated cell responses by functioning as a decoy receptor. OBJECTIVES: To evaluate the expression pattern of endogenous secretory receptor for advanced glycation end products in non-small cell lung carcinoma, and analyze its impact on prognosis. METHODS: We performed immunohistochemical evaluation in 182 non-small cell lung carcinoma surgical specimens. The effect of an overexpressed receptor in cancer cell proliferation was also evaluated. MEASUREMENTS AND MAIN RESULTS: The endogenous secretory receptor for advanced glycation end-product expression in cytoplasm was reduced or absent in 137 of the 182 (75%) carcinomas in contrast to normal lung tissues. mRNA expression was also suppressed in cancer cells. Overexpression of the secretory receptor in lung cancer cell lines had an inhibitory effect on cell proliferation, suggesting the reduced receptor expression accelerated tumor growth. Among patients with low expression of the cytoplasmic secretory receptor, the overall survival rate was significantly lower than that of patients with normal expression (p = 0.0003). This association was most prominent in TNM stage I patients (p = 0.0001). In a multivariate analysis, endogenous secretory receptor immunoreactivity was an independent prognostic factor with a relative risk of 3.1. CONCLUSIONS: The cytoplasmic endogenous secretory receptor for advanced glycation end-product expression has the potential to be a prognostic factor for predicting the outcome of curative surgery in patients with non-small cell lung carcinoma.     

Intramuscular injection of soluble receptor for advanced glycation endproducts expression vector prevents the development of streptozotocin-induced diabetes mellitus in rats on high fat diet

Background: In order to study if advanced glycation endproducts (AGE) in high‐temperature cooked high fat diet could be the cause of type 2 diabetes, a expressing vector encoding soluble form of receptor for AGE (sRAGE) was injected intramuscularly, and the incidence of streptozotocin (STZ)‐induced diabetes mellitus in rats on high fat diet were observed. Methods: Rat sRAGE gene, cloned to a pLNCX₂ expression vector (pLNCX₂‐sRAGE), was injected into the hind leg muscles of Sprague–Dawley rats. Rats were fed with high fat diet for 8 weeks before pLNCX₂‐sRAGE injection (designed as T group), or pLNCX2 (as H group), and rats on normal chow (as N group). The diet remained the same until end of the study. Serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were studied in one serial of rats (n = 8) under the treatment of different vectors without STZ injection. For a second serial of study (n = 20), rats were injected with 30 mg/kg STZ intraperitoneally 2 weeks after the second injection of vectors, and tail blood glucose was detected 1 week later. Results: Malondialdehyde levels were found to be decreased 1 week after injection of sRAGE and lasted for at least 3 weeks after each injection. SOD activities were found to be increased slowly in the second week after each injection. As determined with fasting and random glycemia only two rats were in diabetic level (fasting glycemia ≥7.0 mmol/L and random glycemia ≥11.1 mmol/L) in T group while eight mice were in the diabetic level in H group. Conclusions: Intramuscular injection of sRAGE decreases the MDA level and increases SOD activities, and decreases the STZ‐induced incidence of diabetes in rats in high fat diet.     

Glucose metabolism, advanced glycation endproducts, and cognition

The accumulation of advanced glycation endproducts (AGEs) has been implicated in the pathogenesis of diabetic complications and aging. Diabetes mellitus is associated with moderate cognitive deficit. The AGEs may exert several actions on central nervous system. To explore a possible role of AGEs for cognitive impairment, we have examined the association between serum AGEs and cognitive function in diabetic patients.
We studied 198 diabetic patients with a mean age of 74 years. Serum AGE (N-epsilon- carboxymethyllysine, CML) was measured with the enzyme immunoassay. The several domains of cognitive function were assessed using the WAIS-R, Stroop test, and Benton test. Diabetic patients had more impairment of complex pychomotor skill and visual memory as assessed with the digit symbol substitution test and Benton test than non-diabetic subjects. Among the diabetic patients, a marker of hyperglycemia, HbA1c level was associated with the cognitive impairment, while short-term glucose control partially improved the cognitive impairment. Serum AGE levels correlated with age, duration of diabetes, and HbA1c. Serum AGE levels were significantly associated with the impairment of complex psychomotor skills independent of HbA1c. In conclusion, hyperglycemia and increased AGE accumulation were associated with the cognitive impairment in patients with diabetes mellitus as a model of accelerated aging.     

Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes

Aims/hypothesis Interfering with the activation of receptor for AGE (RAGE) by using a soluble form of the AGE receptor (sRAGE) prevents or ameliorates the vascular complications of diabetes in experimental studies. Relatively little is known about factors that influence endogenous circulating sRAGE in humans. We investigated the impact of improving glycaemic control on serum total sRAGE and endogenous secretory RAGE (esRAGE), a splice variant of sRAGE, and compared the effect of rosiglitazone with that of sulfonylurea. Methods A randomised, open-label, parallel group study was performed with 64 participants randomised to receive add-on therapy with either rosiglitazone or sulfonylurea. Serum total sRAGE and esRAGE and metabolic parameters were measured before and after 6 months of treatment. Results At 6 months, both rosiglitazone and sulfonylurea resulted in a significant reduction in HbA_1c, fasting glucose and AGE. However, significant increases in total sRAGE and esRAGE were only seen in the rosiglitazone group. As a result, serum esRAGE was higher in the rosiglitazone group than in the sulfonylurea group at 6 months (p < 0.01), whereas the differences in sRAGE between the two groups did not reach statistical significance. Stepwise linear regression analysis showed that treatment modality made a greater contribution than the changes in HbA_1c to the subsequent changes in esRAGE levels at 6 months. Conclusions/interpretation Treating type 2 diabetic patients with thiazolidinedione can increase circulating levels of esRAGE and sRAGE. Whether modulation of circulating sRAGE has a beneficial effect on diabetic complications will have to be evaluated in long-term prospective studies. International Standard Randomised Controlled Trial Number ISRCTN05215453.     

Accumulation of advanced glycation endproducts in patients with systemic lupus erythematosus

OBJECTIVE: To investigate whether advanced glycation endproducts (AGEs) are increased in patients with systemic lupus erythematosus (SLE), and are related to atherosclerosis, which is accelerated in SLE, and its traditional and non-traditional disease-related risk factors. METHODS: Fifty-five SLE patients with inactive disease and 55 age- and sex-matched controls were included. The amount of skin autofluorescence (AF), as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS). Traditional risk factors and disease-related factors were recorded. Plasma levels of C-reactive protein (CRP), as a marker for systemic inflammation, were assessed. Intima-media thickness (IMT) of the common carotid artery was determined by ultrasound. RESULTS: Skin AF-EEMS was increased in SLE patients as compared with controls (1.50 +/- 0.5 a.u. vs 1.28 +/- 0.4 a.u., P = 0.006). Regarding all included risk factors, univariate analyses in patients revealed that AF-EEMS was associated with age (r = 0.48, P < 0.001), IMT (r = 0.35, P = 0.01), creatinine (r = 0.29, P = 0.03), SLICC damage index (r = 0.29, P = 0.03) and disease duration (r = 0.32, P = 0.02). In multivariate analysis, age and disease duration were independent predictors of accumulation of AGEs in SLE (P < 0.001, P = 0.03, respectively). CONCLUSION: AGEs are increased in SLE compared with controls. Our findings indicate that AGE accumulation is associated with disease duration and might contribute to the development of accelerated atherosclerosis in SLE and, therefore, could be used for assessment of risk for long-term vascular complications.