Soluble Form Of Receptor For AGEs Research Articles

Advanced glycation end-products change placental barrier function and tight junction in rats with gestational diabetes mellitus via the receptor for advanced glycation end products/nuclear factor-κB pathway

The placenta plays an important role in nutrient transport to maintain the growth and development of the embryo. Gestational diabetes mellitus (GDM), the most common complication during pregnancy, highly affects placental function in late gestation. Advanced glycation end-products (AGEs), a complex and heterogeneous group of compounds engaged by the receptor for AGEs (RAGE), are closely associated with diabetes-related complications. In this study, AGEs induced a decrease in the expression of tight junction (TJ) proteins in BeWo cells and increased the paracellular permeability of trophoblast cells by regulating RAGE/NF-κB. Sprague-Dawley (SD) rats injected with 100 mg/kg AGEs-rat serum albumin (RSA) via the tail vein from embryo day 2 were set as the placental barrier dysfunction model group (n = 10). The effect of AGEs on placental permeability was determined using the EvansBlue dye extravasation method. The ultrastructure of the placenta samples was observed by transmission electron microscopy. The effects of AGEs on the placenta were confirmed by treating rats with RAGE antagonist FPS-ZM1 and soluble forms of RAGE (sRAGE). AGEs treatment increased placental permeability and disrupted the tight junctions in pregnant rat placenta, but has no effect on blood glucose. The expression of TJ-related proteins, including ZO-1, Occludin, and Claudin 5, were downregulated after AGEs treatment. Further, AGEs treatment increased the expression of RAGE and nuclear factor-κB in the placenta of rats and upregulated the levels of vascular endothelial growth factor. The effects of AGEs on the placenta were blocked by RAGE antagonist FPS-ZM1 and sRAGE. This study demonstrates the mechanism underlying AGEs-induced disturbance in placental function in pregnant rats and highlights the potential of AGEs in the treatment of GDM.

Dual Nature of RAGE in Host Reaction and Nurturing the Mother-Infant Bond.

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

Soluble Forms of the Receptor for Advanced Glycation Endproducts (RAGE) in Periodontitis

The receptor for advanced glycation endproducts (RAGE) is critically involved in the pathobiology of chronic inflammatory diseases. Soluble forms of RAGE have been proposed as biomarkers of severity in inflammatory and metabolic conditions, and in monitoring therapeutic responses. The aim of the present study was to determine circulating levels of the soluble forms of RAGE in periodontitis and to evaluate the expression of cell-bound, full-length RAGE and its antagonist AGER1 locally, in gingival tissues. Periodontitis patients and periodontally healthy, sex- and age-matched controls (50 per group) were included. Serum levels of total soluble RAGE and cleaved RAGE (cRAGE) were significantly lower in periodontitis patients. Levels of the endogenous secretory esRAGE were similar in the two groups. cRAGE remained significantly lower in the periodontitis group following multiple adjustments, and had a statistically significant inverse correlation with body mass index and all periodontal parameters. In periodontitis patients, gene expression of full-length RAGE and of AGER1 were significantly higher in periodontitis-affected gingival tissues compared to healthy gingiva. Soluble forms of RAGE, particularly cRAGE, may serve as biomarkers for the presence and severity/extent of periodontitis, and may be implicated in its pathogenesis and its role as a systemic inflammatory stressor.

Identification of a novel advanced glycation end product derived from lactaldehyde.

Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with Nα-acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.

Expression of receptor for advanced glycation end-products (RAGE) in thymus from myasthenia patients

ObjectivesThe receptor for advanced glycation end-products (RAGE) is a membranous immunoglobulin involved in the pathogenesis of numerous autoimmune diseases and tumors. The aim of this study was to investigate the possible involvement of RAGE in the pathogenesis of myasthenia gravis. Material and methodsThis prospective study included 41 cases of myasthenia gravis treated at our institution between 2010 and 2015. There were 18 men and 23 women, with an average age of 36.44±14.47 years. The majority of patients (24.4%) were classified as IIb, according to MGFA scoring, and 21 of them required corticosteroid and/or immunosuppressive treatment. Assessment of RAGE in thymus specimens was done by immunohistochemistry using RAGE antibody (C-term). RAGE expression was assessed according to various clinical, paraclinical and pathological parameters. ResultsHistopathological studies found 18 thymomas, 17 hyperplasias and six other types of pathology. Expression of RAGE was negative/weak in 19 cases and moderate/strong in 22 cases. It was more important in thymoma type B2 (P<0.001) and when the duration of myasthenia was short (P=0.04), and was not significantly related to either myasthenia clinical severity or preoperative treatment. ConclusionOur results suggest that the RAGE pathway is involved in myasthenia gravis pathophysiology, especially at disease onset, and in forms with thymomas. Further studies would be indispensable to explore other aspects of this signaling pathway, especially the potential role of different ligands and soluble forms of RAGE.

Ratio of serum levels of AGEs to soluble RAGE is correlated with trimethylamine-N-oxide in non-diabetic subjects

Trimethylamine (TMA), an intestinal microflora-dependent metabolite formed from phosphatidylcholine- and L-carnitine-rich food, such as red meat, is further converted to trimethylamine-N-oxide (TMAO), which could play a role in cardiometabolic disease. Red meat-derived products are one of the major environmental sources of advanced glycation end products (AGEs) that may also contribute to the pathogenesis of cardiometabolic disorders through the interaction with receptor for AGEs (RAGE). However, the relationship among AGEs, soluble form of RAGE (sRAGE) and TMAO in humans remains unclear. Non-diabetic subjects underwent a physical examination, determination of blood chemistry and anthropometric variables, including AGEs, sRAGE, TMA and TMAO. Multiple regression analyses revealed that HbA1c, uric acid and AGEs were independently associated with log TMA, whereas log AGEs to sRAGE ratio and statin non-use were independently correlated with log TMAO. Our present findings indicated that AGEs to sRAGE ratio was correlated with log TMAO, a marker of cardiometabolic disorders.

Mouse Specific Cleavage-Resistant RAGE Splice Variant.

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

Soluble Levels of Receptor for Advanced Glycation Endproducts (RAGE) and Progression of Atherosclerosis in Individuals Infected with Human Immunodeficiency Virus: ACTG NWCS 332.

Identification of biomarkers and/or mediators of cardiovascular disease (CVD) associated with HIV infection would be of diagnostic and therapeutic value. As soluble receptor for advanced glycation endproducts (sRAGE) and endogenous secretory (esRAGE) have been implicated in vascular complications in other settings, we investigated whether either soluble form of RAGE was associated with changes in carotid intima-media thickness (CIMT) in HIV-infected patients and HIV-uninfected controls. We found no differences in sRAGE, esRAGE, or CIMT among groups at study entry, or in yearly rates of change in sRAGE, esRAGE, or CIMT by HIV-serostatus (all p > 0.10). However, yearly rates of change in sRAGE (p = 0.07) and esRAGE (p < 0.001) were higher in those taking protease inhibitors, and lower baseline esRAGE levels (p = 0.06) were associated with increased odds of CIMT progression in HIV-infected individuals. Although esRAGE was not altered by HIV-serostatus (p = 0.17), its inverse relationship with CIMT progression in HIV-infected patients suggests a possible role as a mediator of CVD in HIV-infected persons.

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

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

An Aqueous Orally Active Vaccine Targeted Against a RAGE/AB Complex as a Novel Therapeutic for Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that gradually destroys a person's memory. Substantial evidence suggests that amyloid beta (Aβ) and the receptor for advanced glycation endproducts (RAGE) play an important and often deleterious role in the pathogenesis of AD. RAGE facilitates the translocation of Aβ from the periphery into the brain, mediates the Aβ-induced neurotoxicity, and enhances the release of pro-inflammatory cytokines increasing the inflammatory response. In addition, soluble forms of RAGE (sRAGE) and Aβ bind together in the periphery forming high molecular weight complexes that are more highly immunogenic and less neurotoxic than Aβ1-42 alone. We show here that there are elevated anti-RAGE and anti-Aβ titers (in a near 1:1 relationship) in samples analyzed from human AD patients, aged non-human primates, and AD transgenic mice (APPSWE-PS1). We show that an in vitro prepared RAGE/Aβ complex induces a greater immunogenic response (increased anti-Aβ1-42 and anti-RAGE antibody titers) in both human peripheral blood mononuclear cells (PBMCs) and immunized Balb-C mice than does either Aβ1-42 or RAGE alone. Further, pretreatment with endogenous anti-RAGE antibodies isolated from our transgenic APPSWE-PS1 mice can prevent Aβ1-42-induced neurotoxicity in cultured primary rat cortical neurons. Finally, we examine the effectiveness of an orally administered vaccine of either RAGE/Aβ complex or Aβ1-42 alone in improving cognitive function in our AD transgenic mice. Our results to date support the hypothesis that a protein complex vaccine that targets both RAGE and Aβ1-42 will provide a more effective treatment for AD than vaccination with Aβ1-42 alone.

Association between sRAGE, esRAGE levels and vascular inflammation: Analysis with 18F-fluorodeoxyglucose positron emission tomography

Background The receptor for advanced glycation end-products (RAGE) and its diverse ligands play a pivotal role in the development of cardiovascular disease. Soluble forms of RAGE (sRAGE), including the splice variant endogenous secretory RAGE (esRAGE), may neutralize AGE-RAGE mediated vascular damage by acting as a decoy. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a novel imaging technique for detecting vascular inflammation. Methods We examined vascular inflammation measured using FDG-PET in 41 type 2 diabetes patients and 41 healthy control subjects in the right carotid artery. Vascular 18F-FDG uptake was measured as the blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). In addition, their relationship with carotid intima-media thickness (CIMT), estimated GFR (eGFR), and other cardiovascular risk factors was evaluated. Results Both mean and maximum TBR values were significantly higher in patients with type 2 diabetes compared to healthy subjects. After adjusting for age and gender, sRAGE levels were significantly correlated with both mean and maximum TBR values, but not with CIMT values. Multiple linear regression analysis showed that maximum TBR values were independently associated with sRAGE levels in addition to HbA1c and eGFR. Conclusions Circulating sRAGE showed significant association with TBR values measured using FDG-PET, which reflect vascular inflammation.

Abstract 4638: Plasma levels of soluble receptor for advanced glycation end-products and risk of colorectal polyps in men

Abstract Background: Receptor for advanced glycation end-products (RAGE) plays an important role in promoting chronic inflammation. Soluble form of RAGE (sRAGE) represents a naturally occurring competitive inhibitor of RAGE-mediated events. We previously found that sRAGE was inversely associated with risk of colorectal cancer in a prospective study among male smokers. However, the relationship between sRAGE and colorectal polyps has not been examined. Methods: In this hospital-based case-control study, we examined the association of plasma levels of sRAGE, along with four soluble receptors of inflammatory cytokines including tumor necrosis factor-α receptor I and II (TNF-αRI and TNF-αRII) and interleukin-6 receptor (IL-6R), with risk of colorectal polyps in general and colon adenoma specifically. During 2008- 2010, we identified men with pathologically confirmed colorectal polyp as cases and those with no polyps as controls among prospectively enrolled men who underwent screening colonoscopy. We excluded men with clinical confirmed type 2 diabetes and serum creatinine &amp;gt; 1.2 mg/dl. A total of 73 cases (50 with adenoma) and 62 controls were included in the present analysis. Cases and controls were frequency-matched according to age and race. Plasma samples were obtained at time of colonoscopy and exposure information was collected using interviewer-administered questionnaire. We used multiplex-ELISA to determine plasma level of serological biomarkers. Multivariate logistic regression model adjusting for age, race, smoking status and body mass index was used to estimate odds ratio (OR) and its 95% confidence interval (CI). Results: The median age was 61.0 years for both groups. sRAGE had no correlation with TNF-RI, TNF-RII, and sIL-6R levels among controls. Cases had significantly lower levels of sRAGE than controls (P value for rank sum test = 0.01). When highest compared with lowest tertile of sRAGE, the OR (95% CI) was 0.28 (0.11-0.73) (P trend = 0.004) for colorectal polyps and 0.22 (0.06-0.85) (P trend =0.001) for adenoma. sIL-6R had statistically non-significant positive association with risk of colorectal polyps (OR = 1.65, 95% CI = 0.63-4.32, P trend = 0.30) and adenoma (OR = 2.49, 95% CI = 0.81 -7.60, P trend = 0.09) respectively. Plasma levels of TNF-RI and TNF-RII had no association with risk of colorectal polyps. Conclusion: This study suggests a protective role of sRAGE, an anti-inflammatory factor, for precursor lesions of colorectal cancer in men. Our finding is in line with the previous study that showed an inverse association between sRAGE and colorectal cancer. As a modifiable target, the role of sRAGE in colorectal carcinogenesis deserves further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2011-4638

Soluble forms of RAGE in internal medicine

The receptor for advanced glycation end-products (RAGE) and its ligands are intimately involved in the pathobiology of a wide range of diseases that share common features, such as enhanced oxidative stress, immune/inflammatory responses, and altered cell functions. Soluble forms of RAGE (sRAGE), including the splice variant endogenous secretory (es)RAGE, have been found circulating in plasma and tissues. Experimental data suggest that these isoforms may neutralize the ligand-mediated damage by acting as a decoy. Moreover, evidence is mounting to support a role for both sRAGE and esRAGE as biomarkers or endogenous protection factors against RAGE-mediated pathogenesis. In this review, we will focus on clinical and therapeutical implications arising from studies investigating the significance of soluble RAGE isoforms in several clinical settings, including cardiovascular disease, diabetes mellitus, hypercholesterolemia, chronic renal failure, immune/inflammatory diseases, pulmonary diseases, neurodegeneration, and cancer.

Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases

The formation of advanced glycation end products (AGEs) is a result of the non-enzymatic reaction between sugars and free amino groups of proteins. AGEs, through interacting with their specific receptor for AGEs (RAGE), result in activation of pro-inflammatory states and are involved in numerous pathologic situations. The soluble form of RAGE (sRAGE) is able to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands (AGEs, HMGB1, S100 proteins). sRAGE levels have been found to be decreased in chronic inflammatory diseases including atherosclerosis, diabetes, renal failure and the aging process. The use of measuring circulating sRAGEs may prove to be a valuable vascular biomarker and in this review, we describe the implications of sRAGE in inflammation and propose that this molecule may represent a future therapeutic target in chronic inflammatory diseases.

Endogenous secretory RAGE but not soluble RAGE is associated with carotid atherosclerosis in type 1 diabetes patients

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system play an important role in the development of diabetic complications. The soluble form of RAGE (sRAGE) that potentially counteracts AGEs consists of several forms, including endogenous secretory RAGE (esRAGE; a splice variant of RAGE) and cleaved-type soluble RAGE derived from cell-surface RAGE. The aim of this study was to compare sRAGE and esRAGE directly in patients with type 1 diabetes. The associations of both total sRAGE and esRAGE with markers of glycaemic control and with carotid intima-media thickness (IMT) as a marker of atherosclerosis were examined in 130 type 1 diabetes patients (aged 23.6+/-4.9 years) and 22 age-matched non-diabetic subjects. IMT was inversely correlated with esRAGE (r=-0.254, p=0.0015) but neither with sRAGE nor subtracted soluble RAGE values (that is, circulating total sRAGE values - circulating esRAGE values). Furthermore, a stepwise multivariate regression analysis revealed that esRAGE (F=7.3), but not sRAGE, was a variable that interacted independently of IMT. It is likely that circulating sRAGE and esRAGE are distinct markers and that circulating esRAGE levels, but not sRAGE levels, are associated with the status of early-stage atherosclerosis.

Soluble RAGE: a hot new biomarker for the hot joint?

The receptor for advanced glycation endproducts (RAGE) interacts with distinct ligand families linked to the inflammatory response. Studies in animal models suggest that RAGE is upregulated in the inflamed joint and that blockade of the receptor, using a ligand decoy soluble form of RAGE (sRAGE), attenuates joint inflammation and expression of inflammatory and tissue-destructive mediators. In this issue of Arthritis Research & Therapy, Rille Pullerits and colleagues reported that plasma levels of sRAGE were reduced in subjects with rheumatoid arthritis compared with healthy controls or subjects with non-inflammatory joint disease. These findings suggest the possibility that levels of sRAGE might be a biomarker of inflammation. Not resolved by these studies, however, is the intriguing possibility that endogenously higher levels of sRAGE might be linked to a lower incidence of arthritis or to the extent of inflammation. Nevertheless, although 'cause or effect' relationships may not be established in this report, fascinating insights into RAGE, inflammation and human arthritis emerge from these studies.

Use of topical sRAGE in diabetic wounds increases neovascularization and granulation tissue formation.

Advanced glycation end products (AGEs) accumulate in diabetic wounds as a result of the glycosylation of various proteins. Interaction of AGEs with the receptor for AGEs (RAGE) results in an exaggerated inflammatory response and compromised collagen production. These changes lead to impaired wound healing. A soluble form of RAGE (sRAGE) has been shown to bind AGEs and thereby blunt their pathogenetic effects. Using genetically diabetic C57BLks-db/db mice, the authors applied sRAGE topically to standardized full-thickness wounds to improve diabetic wound healing. They measured various parameters of wound healing such as neovascularization, reepithelialization, collagen formation, and granulation tissue area. Their results showed a statistically significant increase in granulation tissue area and microvascular density in the sRAGE group compared with untreated wounds. There was a trend toward a smaller epithelial gap in the sRAGE-treated group that did not reach statistical significance. The authors conclude that sRAGE may be a powerful treatment of accelerating diabetic wound healing.

Identification of a novel AGE-capturable soluble variant of the RAGE in human sera

Engagement by advanced glycation endproducts (AGE) of the cell surface receptor for AGE (RAGE) leads to perturbation of vascular cell functions. This includes proliferation of endothelial cells (EC), and decrease in pericytes. To clarify these different cellular responses, we analyzed in this study polysomal mRNAs for RAGE from human microvascular EC and pericytes by RT-PCR cloning, and isolated three major variants: novel C-terminally and N-terminally truncated forms and the known full-length form. The protein product of the C-terminally truncated variant was secreted into culture media, whereas the N-terminally truncated form resided on the plasma membrane, when each cDNA was forced to be expressed in COS-7 cells. The former, soluble form of RAGE was actually detected in healthy human sera, and was found capable of neutralizing AGE induction of vascular endothelial growth factor (VEGF) gene in EC. Different degrees of the expression of those RAGE variants may elicit different cellular responses to AGE, and such variation may contribute to the individual susceptibility or resistance to the development of diabetic complications.