Soluble receptors for advanced glycation end-products prevent unilateral ureteral obstruction-induced renal fibrosis.

Introduction: The receptor for advanced glycation end products (RAGE) and its ligands, such as high-mobility group protein box 1 (HMGB1), play an important role in the accumulation of extracellular matrix in chronic kidney diseases with tubulointerstitial fibrosis. Blocking RAGE signaling with soluble RAGE (sRAGE) is a therapeutic candidate for renal fibrosis. Methods: NRK-52E cells were stimulated with or without HMGB1 and incubated with sRAGE in vitro. Sprague-Dawley rats were intraperitoneally treated with sRAGE after unilateral ureteral obstruction (UUO) operation in vivo. Results: HMBG1-stimulated NRK-52E cells showed increased fibronectin expression, type I collagen, α-smooth muscle actin, and connective tissue growth factor, which were attenuated by sRAGE. The mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of nuclear factor kappa B (NF-κB) were enhanced in NRK-52E cells exposed to HMBG1, and sRAGE treatment alleviated the activation of the MAPK and NF-κB pathways. In the UUO rat models, sRAGE significantly ameliorated the increased renal fibronectin, type I collagen, and α-smooth muscle actin expressions. Masson's trichrome staining confirmed the anti-fibrotic effect of sRAGE in the UUO rat model. RAGE also significantly attenuated the activation of the MAPK pathway and NF-κB, as well as the increased number of infiltrated macrophages within the tubulointerstitium in the kidney of the UUO rat models. Conclusion: These findings suggest that RAGE plays a pivotal role in the pathogenesis of renal fibrosis and that its inhibition by sRAGE may be a potential therapeutic approach for renal fibrosis.

RAGE Inhibitors in Neurodegenerative Diseases.

Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer's disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood-brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE-RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE-RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE-RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.

A Study on the Protective Effect of sRAGE-MSCs in a Rodent Reperfusion Model of Myocardial Infarction.

Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases.

Reduced Circulating Soluble Receptor for Advanced Glycation End-products in Chronic Hepatitis B Are Associated with Hepatic Necroinflammation.

The diagnosis and disease management of chronic hepatitis B (CHB) remain challenging due to the elusive assessment of disease severity. Recently, soluble receptor for advanced glycation end-products (sRAGE) has been implicated in the inflammatory-immune response initiated by liver injury. Nonetheless, its natural behavior and clinical importance in CHB remain elusive. One hundred and twenty CHB patients and forty healthy controls (HCs) were enrolled, and the serum sRAGE as well as RAGE expression in biopsy specimens from these subjects was analyzed, and correlation of sRAGE with clinical features as well as its potential predictive value for monitoring the CHB was also evaluated. Reduced serum sRAGE levels and decreased tissular RAGE expression were observed in CHB patients. sRAGE and RAGE were inversely correlated with gradually increased grades of hepatic necroinflammation as well as the routine indicator ALT. Furthermore, receiver operating characteristic (ROC) analysis showed that combination of ALT and sRAGE exerted better predictive power (area under the ROC curve (AUC) of 0.86) for hepatic necroinflammation than that of ALT (AUC of 0.82), sRAGE (AUC of 0.81), or sRAGE-to-ALT ratio (sRAGE/ALT) (AUC of 0.85) alone. More importantly, circulating sRAGE alone exerted valuable predictive power for hepatic moderate-to-severe necroinflammation in CHB patients but with normal ALT (AUC of 0.81) or minimally elevated ALT (AUC of 0.85). In conclusion, reduced serum sRAGE levels may imply an increased severity for necroinflammation, and it may serve as a potential alternative biomarker for monitoring hepatic necroinflammation in CHB.

Skin autofluorescence corresponds to microvascular reactivity in diabetes mellitus.

Advanced glycation accelerated by chronic hyperglycaemia contributes to the development of diabetic vascular complications throughout several mechanisms. One of these mechanisms is supposed to be impaired microvascular reactivity, that precedes significant vascular changes. The aim of this study was to find an association between advanced glycation, the soluble receptor for AGEs (sRAGE), and microvascular reactivity (MVR) in diabetes. Skin autofluorescence (SAF), which reflects advanced glycation, was assessed by AGE-Reader, MVR was measured by laser Doppler fluxmetry and evaluated together with sRAGE in 43 patients with diabetes (25 Type 1 and 18 Type 2) and 26 healthy controls of comparable age. SAF was significantly higher in patients with diabetes compared to controls (2.4 ± 0.5 vs. 2.0 ± 0.5 AU; p < 0.01). Patients with diabetes with SAF > 2.3 AU presented significantly worse MVR in both post-occlusive reactive hyperaemia (PORH) on the finger and forearm, and thermal hyperaemia (TH), compared to patients with SAF < 2.3 AU. SAF was age dependent in both diabetes (r = 0.41, p < 0.01) and controls (r = 0.45, p < 0.05). There was no association between SAF and diabetes control expressed by glycated haemoglobin. A significant relationship was observed between SAF and sRAGE in diabetes (r = 0.56, p < 0.001), but not in controls. A significant inverse association was found between SAF and MVR on the forearm in diabetes (PORH: r = -0.42, p < 0.01; TH: r = -0.46, p < 0.005). Both advanced glycation expressed by higher SAF or sRAGE and impaired MVR are involved in the pathogenesis of vascular complications in diabetes, and we confirm a strong interplay of these processes in this scenario.

Plasma advanced glycation end products and soluble receptor for advanced glycation end products as indicators of sterol content in human carotid atherosclerotic plaques.

Advanced glycation end products (AGEs) are independently related to cardiovascular disease (CVD) and favor cholesterol and oxysterol accumulation in macrophage foam cells. Soluble RAGE (sRAGE) impairs cellular AGE signaling alleviating the deleterious effects of AGE in atherogenesis. The association between plasma AGEs and sRAGE with the content of cholesterol, markers of cholesterol synthesis and absorption, and oxysterols in atherosclerotic plaques was evaluated in subjects undergoing carotid endarterectomy.Plasma and carotid plaques were obtained from symptomatic (n = 23) and asymptomatic subjects (n = 40). Lipids from plaques were extracted and sterols (oxysterols, cholesterol, desmosterol, lathosterol, sitosterol, and campesterol) were determined by using gas chromatography/mass spectrometry. Plasma total AGEs and pentosidine were measured by using fluorimetry and sRAGE by using ELISA.In symptomatic subjects´ atherosclerotic plaques, an increased amount of cholesterol (3x) and oxysterols [7 α-hydroxycholesterol (1.4x); 7 ß-hydroxycholesterol (1.2x); 25-hydroxycholesterol (1.3x); 24-hydroxycholesterol (2.7x), and 27-hydroxycholesterol, (1.15x)], with exception to 7 ketocholesterol, were found in comparison to asymptomatic individuals. Plasma total AGEs and pentosidine significantly and positively correlated to sterols accumulated in the atherosclerotic lesion, including cholesterol, desmosterol, campesterol, sitosterol, and oxysterols. On the other hand, sRAGE inversely correlated to total AGEs and pentosidine in plasma, and with major species of oxysterols, cholesterol, and markers of cholesterol synthesis and absorption in the atherosclerotic lesion. In multiple regression analyses, it was observed a significant inverse correlation between sRAGE and 24-hydroxycholesterol and desmosterol, and a positive significant correlation between pentosidine and 24-hydroxycholesterol, 27-hydroxycholesterol, and campesterol.In conclusion, the plasma concentration of AGEs and sRAGE is a tool to predict the accumulation of sterols in atherosclerotic lesions in symptomatic and asymptomatic individuals, helping to prevent and improve the management of acute cardiovascular complications.

Soluble RAGE attenuates Ang II-induced arterial calcification via inhibiting AT1R-HMGB1-RAGE axis.

BACKGROUND AND AIMS: Arterial calcification (AC), which is an important process in the pathogenesis of atherosclerosis, is accelerated by angiotensin II (Ang II), a critical effector of the renin-angiotensin system (RAS). Receptor for advanced glycation end-product (RAGE) is an important pattern recognition receptor downstream of Ang II. Although recent studies have suggested an association between RAGE-mediated signaling and RAS in AC, the detailed mechanism, particularly in relation to Ang II, remains unclear. METHODS: Therefore, we investigated the role of RAGE-mediated signaling pathways and the therapeutic efficacy of soluble RAGE (sRAGE) in Ang II-induced AC, using both a human aortic smooth muscle cell (HAoSMC) model, and an in vivo apolipoprotein E knockout (ApoE KO) mouse model. RESULTS: According to our data, Ang II significantly increased the calcification of HAoSMCs, and the associated activation of RAGE was mediated by subsequent HMGB1 release through Angiotensin II type 1 receptor activation. Both HMGB1 neutralizing antibody and sRAGE inhibited Ang II-induced calcium deposition. Furthermore, sRAGE attenuated HMGB1 secretion and the activation of RAGE-mediated signaling. The in vivo study indicated that Ang II significantly induced calcium deposition in the aorta, and this was significantly attenuated by sRAGE. CONCLUSIONS: Our findings strongly suggest that blockade of RAGE, using sRAGE, effectively attenuates Ang II-induced arterial calcification.

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

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

Changes in Plasma Soluble Receptor for Advanced Glycation End-Products Are Associated with Survival in Patients with Acute Respiratory Distress Syndrome.

The plasma soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury with prognostic value when measured at baseline in acute respiratory distress syndrome (ARDS). However, whether changes in plasma sRAGE could inform prognosis in ARDS remains unknown. In this secondary analysis of the Lung Imaging for Ventilator Setting in ARDS (LIVE) multicenter randomized controlled trial, which evaluated a personalized ventilation strategy tailored to lung morphology, plasma sRAGE was measured upon study entry (baseline) and on days one, two, three, four and six. The association between changes in plasma sRAGE over time and 90-day survival was evaluated. Higher baseline plasma sRAGE (HR per-one log increment, 1.53; 95% CI, 1.16-2.03; p = 0.003) and an increase in sRAGE over time (HR for each one-log increment in plasma sRAGE per time unit, 1.01; 95% CI, 1.01-1.02; p < 10-3) were both associated with increased 90-day mortality. Each 100-unit increase in the plasma sRAGE level per unit of time increased the risk of death at day 90 by 1% in joint modeling. Plasma sRAGE increased over time when a strategy of maximal alveolar recruitment was applied in patients with focal ARDS. Current findings suggest that the rate of change in plasma sRAGE over time is associated with 90-day survival and could be helpful as a surrogate outcome in ARDS.

Association analysis of -429T/C receptor for advanced glycation end products (RAGE) gene polymorphism with type 2 diabetic retinopathy and serum soluble RAGE levels in Pakistani patients.

OBJECTIVE: To investigate the association of receptor for advanced glycation end products gene polymorphism 429T/C (rs1800625) with diabetic retinopathy and serum soluble receptor for advanced glycation end products levels in patients with type 2 diabetes. METHODS: The case-control study was conducted from January 2017 to December 2018 at Pakistan Railway Hospital, Rawalpindi, and the Multidisciplinary Laboratories of Islamic International Medical College, Riphah International University (RIU), Islamabad, Pakistan. Those included were healthy controls in group A, diabetics without retinopathy in group B and patients having diabetic retinopathy in group C. Genotyping for 429T/C was done by tetra-primer amplification refractory mutation system-polymerase chain reaction. Serum soluble receptor for advanced glycation end products levels were measured using enzyme-linked immunosorbent assay. Data was analysed using SPSS 22. RESULTS: Of the 450 subjects, 150(33.3%) were in each of the three groups. The frequency of TT, TC and CC genotypes of 429T/C polymorphism were 137(91.3%), 10(6.7%) and 3(2%) in group A; 133(88.6%), 13(8.7%) and 4(2.7%) in group B; and 127(84.7%), 18(12%) and 5(3.3%) in group C. No significant association of 429T/C genotypic and allelic frequencies were found with groups B and C (p>0.05). Serum soluble receptor for advanced glycation end products levels were significantly high in patients with proliferative diabetic retinopathy and were positively correlated with fasting plasma glucose in group C (p<0.05). TC and CC genotypes were significantly associated with raised serum soluble receptor for advanced glycation end products, and TC with raised fasting plasma glucose in group C. CONCLUSIONS: The 429T/C receptor for advanced glycation end products gene polymorphism was found to be associated with severe non-proliferative diabetic retinopathy, and serum soluble receptor for advanced glycation end products levels had a positive correlation with severity of diabetic retinopathy.

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COVID-19 disease severity and indicator of the need for mechanical ventilation, ARDS and mortality.

BACKGROUND: COVID-19 pneumonia and subsequent respiratory failure is causing an immense strain on intensive care units globally. Early prediction of severe disease enables clinicians to avoid acute respiratory distress syndrome (ARDS) development and improve management of critically ill patients. The soluble receptor of advanced glycation endproducts (sRAGE) is a biomarker shown to predict ARDS. Although sRAGE level varies depending on the type of disease, there is limited information available on changes in sRAGE levels in COVID-19. Therefore, sRAGE was measured in COVID-19 patients to determine sRAGE level variation in COVID-19 severity and to examine its ability to predict the need for mechanical ventilation (MV) and mortality in COVID-19. METHODS: In this single-centre observational cohort study in Germany, serum sRAGE during acute COVID-19, 20 weeks after the start of COVID-19 symptoms, as well as in control groups of non-COVID-19 pneumonia patients and healthy controls were measured using ELISA. The primary endpoint was severe disease (high-flow nasal oxygen therapy (HFNO)/MV and need of organ support). The secondary endpoints were respiratory failure with need of MV and 30-day mortality. The area under the curve (AUC), cut-off based on Youden's index and odds ratio with 95% CI for sRAGE were calculated with regard to prediction of MV need and mortality. RESULTS: Serum sRAGE in 164 COVID-19 patients, 101 matched COVID-19 convalescent patients, 23 non-COVID-19 pneumonia patients and 15 healthy volunteers were measured. sRAGE level increased with COVID-19 severity, need for oxygen therapy, HFNO/MV, ARDS severity, need of dialysis and catecholamine support, 30-day mortality, sequential organ failure assessment (SOFA) and quick SOFA (qSOFA) score. sRAGE was found to be a good predictor of MV need in COVID-19 inpatients and mortality with an AUC of 0.871 (0.770-0.973) and 0.903 (0.817-0.990), respectively. When adjusted for male gender, age, comorbidity and SOFA score ≥ 3, sRAGE was independently associated with risk of need for HFNO/MV. When adjusted for SOFA score ≥ 3, sRAGE was independently associated with risk of need for MV. CONCLUSIONS: Serum sRAGE concentrations are elevated in COVID-19 patients as disease severity increases. sRAGE should be considered as a biomarker for predicting the need for MV and mortality in COVID-19.

Galectin-3 and soluble RAGE as new biomarkers of post-infarction cardiac remodeling.

Post-infarction remodeling is a clinical problem with no curative treatment. Our objective was to search for new biomarkers of cardiac remodeling that have clinical value after ST-segment elevation myocardial infarction (STEMI). This pilot study enrolled 67 consecutive patients with de novo STEMI who underwent revascularization by primary angioplasty. Echocardiography studies of cardiac function were completed during the first 48 h post-STEMI and after 6 months of follow-up. Galectin-3 and soluble receptor for advanced glycation end products (sRAGE) were tested in the peripheral venous blood during the 24 h post-infarction. Cardiac remodeling was defined as changes ≥ 15% in the left ventricular end-systolic volume (LVESV) or > 10% in the left atrial area (LAA). An inverse association was found between galectin-3 (rs = - 0.296; p < 0.001) and sRAGE (rs = - 0.327; p < 0.001) levels and the basal left ventricle ejection fraction (LVEF). However, only galectin-3 was directly associated with the increase in LVESV (rs = 0.389; p = 0.007) and LVEDV (rs = 0.314; p = 0.031) during the follow-up. sRAGE was inversely related to the change in LAA (rs = - 0.320; p = 0.032). These data are consistent with galectin-3, but not sRAGE levels, as a predictor of left ventricle remodeling (OR 1.036, 95% CI 1.002-1.071; p = 0.039). Galectin-3 and sRAGE levels that were measured during hospitalization are inversely related to basal LVEF after a STEMI. Galectin-3 levels are a predictor of adverse post-STEMI LV remodeling, whereas sRAGE levels exhibited an inverse relationship with left atrial remodeling. KEY MESSAGES: Post-infarction remodeling is a clinical problem with no curative treatment. New biomarkers for remodeling after acute myocardial infarction were explored. Early post-STEMI galectin-3 and soluble RAGE are inversely related with left ventricle function. Galectin-3 levels were predictors of adverse post-STEMI left ventricle remodeling. Soluble RAGE levels were associated with left atrial remodeling.

AGE-RAGE Stress in the Pathophysiology of Atrial Fibrillation and Its Treatment.

Atrial fibrillation (AF) is the most common of cardiac arrhythmias. Mechanisms such as atrial structural remodeling and electrical remodeling have been implicated in the pathogenesis of AF. The data to date suggest that advanced glycation end products (AGEs) and its cell receptor RAGE (receptor for AGE) and soluble receptor (sRAGE) are involved in the pathogenesis of AF. This review focuses on the role of AGE-RAGE axis in the pathogenesis of AF. Interaction of AGE with RAGE generates reactive oxygen species, cytokines, and vascular cell adhesion molecules. sRAGE is a cytoprotective agent. The data show that serum levels of AGE and sRAGE, and expression of RAGE, are elevated in AF patients. Elevated levels of sRAGE did not protect the development of AF. This might be due to greater elevation of AGE than sRAGE. Measurement of AGE-RAGE stress (AGE/sRAGE) would be appropriate as compared with measurement of AGE or RAGE or sRAGE alone in AF patients. AGE and its interaction with RAGE can induce AF through alteration in cellular protein and extracellular matrix. AGE and its interaction with RAGE induce atrial structural and electrical remodeling. The treatment strategy should be directed toward reduction in AGE levels, suppression of RAGE expression, blocking of binding of AGE to RAGE, and elevation of sRAGE and antioxidants. In conclusion, AGE-RAGE axis is involved in the development of AF through atrial structural and electrical remodeling. The treatment modalities for AF should include lowering of AGE, suppression of RAGE, elevation of sRAGE, and use of antioxidants.

Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis.

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients. Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed. Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years. Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD. Trial registration: ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018.

Soluble receptor for advanced glycation end products as a biomarker of symptomatic vasospasm in subarachnoid hemorrhage.

OBJECTIVE: The receptor for advanced glycation end products (RAGE) is a membrane protein associated with the induction of oxidative stress and inflammation in several pathological conditions. Previous studies have demonstrated that soluble RAGE (sRAGE) acts as a decoy for RAGE and protects cells against RAGE-mediated injury. The authors and other groups have reported that the expression of RAGE increases after brain ischemia and subarachnoid hemorrhage (SAH), and deletion of RAGE or overexpression of sRAGE improves neuronal survival. It has also been demonstrated that the plasma sRAGE level could be a predictor of the outcome after ischemic stroke. This study aimed to evaluate plasma sRAGE as a biomarker for symptomatic vasospasm (SVS) in SAH patients, as well as a rat model. METHODS: The authors measured and compared plasma sRAGE levels in 27 SAH patients (7 with SVS and 20 without SVS) from day 5 to day 14 post-SAH. They also examined plasma sRAGE levels and expression of RAGE and heme oxygenase-1 (HO-1) in a rat SAH model. RESULTS: The relative plasma sRAGE levels were significantly lower in the SVS group than in the non-SVS group of patients. A cut-off value of 0.84 for predicting SVS was considered to be appropriate for the relative plasma sRAGE levels on day 7 versus day 5. In the rat SAH model, plasma sRAGE levels were significantly lower than those in sham-treated rats, and the expressions of RAGE and HO-1 were enhanced in the SAH group compared with the non-SAH group. CONCLUSIONS: Plasma sRAGE levels can be used as a potential biomarker for predicting SVS after SAH.

AGE-RAGE Stress in the Pathophysiology of Pulmonary Hypertension and its Treatment.

Pulmonary hypertension (PH) is a rare and fatal disease characterized by elevation of pulmonary artery pressure ≥ 25 mm Hg. There are five groups of PH: (1) pulmonary artery (PA) hypertension (PAH), (2) PH due to heart diseases, (3) PH associated with lung diseases/hypoxia, (4) PH associated with chronic obstruction of PA, and (5) PH due to unclear and/or multifactorial mechanisms. The pathophysiologic mechanisms of group 1 have been studied in detail; however, those for groups 2 to 5 are not that well known. PH pathology is characterized by smooth muscle cells (SMC) proliferation, muscularization of peripheral PA, accumulation of extracellular matrix (ECM), plexiform lesions, thromboembolism, and recanalization of thrombi. Advanced glycation end products (AGE) and its receptor (RAGE) and soluble RAGE (sRAGE) appear to be involved in the pathogenesis of PH. AGE and its interaction with RAGE induce vascular hypertrophy through proliferation of vascular SMC, accumulation of ECM, and suppression of apoptosis. Reactive oxygen species (ROS) generated by interaction of AGE and RAGE modulates SMC proliferation, attenuate apoptosis, and constricts PA. Increased stiffness in the artery due to vascular hypertrophy, and vasoconstriction due to ROS resulted in PH. The data also suggest that reduction in consumption and formation of AGE, suppression of RAGE expression, blockage of RAGE ligand binding, elevation of sRAGE levels, and antioxidants may be novel therapeutic targets for prevention, regression, and slowing of progression of PH. In conclusion, AGE-RAGE stress may be involved in the pathogenesis of PH and the therapeutic targets should be the AGE-RAGE axis.

Metabolic dysfunction in Emirati subjects in Abu Dhabi: Relationship to levels of soluble RAGEs.

BACKGROUND: The United Arab Emirates is experiencing increasing rates of type 2 diabetes (T2D) and its complications. As soluble levels of the receptor for advanced glycation end products, (sRAGE), and endogenous secretory RAGE (esRAGE), the latter an alternatively spliced form of AGER (the gene encoding RAGE), have been reported to be associated with T2D and its complications, we tested for potential relationships between these factors and T2D status in Emirati subjects. METHODS: In a case-control study, we recruited Emirati subjects with T2D and controls from the Sheikh Khalifa Medical City in Abu Dhabi. Anthropomorphic characteristics, levels of plasma sRAGE and esRAGE, and routine chemistry variables were measured. RESULTS: Two hundred and sixteen T2D subjects and 215 control subjects (mean age, 57.4 ±â€¯12.1 vs. 50.7 ±â€¯15.4 years; P < 0.0001, respectively) were enrolled. Univariate analyses showed that levels of sRAGE were significantly lower in the T2D vs. control subjects (1033.9 ±â€¯545.3 vs. 1169.2 ±â€¯664.1 pg/ml, respectively; P = 0.02). Multivariate analyses adjusting for age, sex, systolic blood pressure, pulse, body mass index, Waist/Hip circumference ratio, fasting blood glucose, HDL, LDL, insulin, triglycerides, Vitamin D and urea levels revealed that the difference in sRAGE levels between T2D and control subjects remained statistically-significant, P = 0.03, but not after including estimated glomerular filtration rate in the model, P = 0.14. There were no significant differences in levels of esRAGE. Levels of plasma insulin were significantly higher in the control vs. the T2D subjects (133.6 ±â€¯149.9 vs. 107.6 ±â€¯93.3 pg/L. respectively; P = 0.01, after adjustment for age and sex). CONCLUSION/DISCUSSION: Levels of sRAGE, but not esRAGE, were associated with T2D status in Abu Dhabi, but not after correction for eGFR. Elevated levels of plasma insulin in both control and T2D subjects suggests the presence of metabolic dysfunction, even in subjects without diabetes.

Experimental Hyperglycemia Alters Circulating Concentrations and Renal Clearance of Oxidative and Advanced Glycation End Products in Healthy Obese Humans.

The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m-2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma at basal and after 2 h and 24 h of hyperglycemic challenge were assayed for OX (methionine sulfoxide, MetSO, and aminoadipic acid, AAA) and AGE-free adducts (Ne-carboxymethyllysine, CML; Ne-carboxyethyllysine, CEL; glyoxal hydroimidazolone-1, GH-1; methylglyoxal hydroimidazolone-1, MG-H1; and 3-deoxyglucosone hydroimidazolone, 3DG-H) via liquid chromatography⁻tandem mass spectrometry (LC⁻MS/MS). Urine was also analyzed at basal and after 24 h for OX and AGE-free adducts and plasma soluble RAGE (sRAGE) isoforms (endogenous secretory RAGE, esRAGE, and cleaved RAGE, cRAGE), and inflammatory markers were determined via enzyme-linked immunosorbent assay (ELISA). Skeletal muscle tissue collected via biopsy was probed at basal, 2 h, and 24 h for RAGE and OST48 protein expression. Plasma MetSO, AAA, CEL, MG-H1, and G-H1 decreased (-18% to -47%; p < 0.05), while CML increased (72% at 24 h; p < 0.05) and 3DG-H remained unchanged (p > 0.05) with the hyperglycemic challenge. Renal clearance of MetSO, AAA, and G-H1 increased (599% to 1077%; p < 0.05), CML decreased (-30%; p < 0.05), and 3DG-H, CEL, and MG-H1 remained unchanged (p > 0.05). Fractional excretion of MetSO, AAA, CEL, G-H1, and MG-H1 increased (5.8% to 532%; p < 0.05) and CML and 3DG-H remained unchanged (p > 0.05). Muscle RAGE and OST48 expression, plasma sRAGE, IL-1ß, IL-1Ra, and TNFα remained unchanged (p > 0.05), while IL-6 increased (159% vs. basal; p > 0.05). These findings suggest that individuals who are obese but otherwise healthy have the capacity to prevent accumulation of OX and AGEs during metabolic stress by increasing fractional excretion and renal clearance.

Divergent Changes in Plasma AGEs and sRAGE Isoforms Following an Overnight Fast in T1DM.

Advanced glycation end products (AGEs) promote the development of diabetic complications through activation of their receptor (RAGE). Isoforms of soluble RAGE (sRAGE) sequester AGEs and protect against RAGE-mediated diabetic complications. We investigated the effect of an overnight fast on circulating metabolic substrates, hormones, AGEs, and sRAGE isoforms in 26 individuals with type 1 diabetes (T1DM). Blood was collected from 26 young (18⁻30 years) T1DM patients on insulin pumps before and after an overnight fast. Circulating AGEs were measured via LC-MS/MS and sRAGE isoforms were analyzed via ELISA. Glucose, insulin, glucagon, and eGFRcystatin-c decreased while cortisol increased following the overnight fast (p < 0.05). AGEs (CML, CEL, 3DG-H, MG-H1, and G-H1) decreased (21⁻58%, p < 0.0001) while total sRAGE, cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE) increased (22⁻24%, p < 0.0001) following the overnight fast. The changes in sRAGE isoforms were inversely related to MG-H1 (rho = -0.493 to -0.589, p < 0.05) and the change in esRAGE was inversely related to the change in G-H1 (rho = -0.474, p < 0.05). Multiple regression analyses revealed a 1 pg/mL increase in total sRAGE, cRAGE, or esRAGE independently predicted a 0.42⁻0.52 nmol/L decrease in MG-H1. Short-term energy restriction via an overnight fast resulted in increased sRAGE isoforms and may be protective against AGE accumulation.

Role of Receptors for Advanced Glycation End Products and High-Mobility Group Box 1 in the Outcome of Human T Cell Lymphotropic Type 1 Infection.

Human T cell lymphotropic type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic viral neuroinflammatory disease, which leads to damage of the central nervous system. Inflammatory responses and mediators are both involved in the pathogenesis of the disease and in determining its outcome. High-Mobility Group Box 1 (HMGB1) is a chromatin-associated nuclear protein acting as a signaling molecule in cells after binding to its receptors. Receptor for advanced glycation end products (RAGE) is a transmembrane multiligand receptor that binds to HMGB1. HMGB1-RAGE signaling has an important role in inflammatory and infectious diseases. Inhibition of HMGB1 activity reduces the inflammation in immune-associated diseases. In the present study, we examined the gene expressions and plasma levels of HMGB1 and its receptor RAGE in HAM/TSP patients, HTLV-1-infected asymptomatic carriers (ACs), and healthy controls. Peripheral blood mononuclear cells were collected from all the groups and complementary DNA (cDNA) was synthesized. HMGB-1 messenger RNA (mRNA) expression was quantified by real-time polymerase chain reaction (PCR) TaqMan method, and plasma levels of HMGB1 and soluble RAGE (sRAGE) were measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of HMGB1 was the same among the groups (p > 0.05). No significant difference in the plasma levels of HMGB1 was observed between the groups (p > 0.05). The plasma levels of sRAGE were higher in ACs than HAM/TSP patients, and a significant difference was observed between the two groups (p < 0.001). Our results showed that sRAGE could play a potential role in the control of inflammatory response in HTLV-1 carriers through the inhibition of HMGB1 signaling and potentially could be used as an indicator for evaluation of HAM/TSP developing in HTLV-1-infected individuals.