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Satellite Cell Expression of RAGE (Receptor for Advanced Glycation end Products) Is Important for Collateral Vessel Formation.

ABSTRACT: Background The growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is RAGE (receptor for advanced glycation end products). This study sought to determine the cellular source of RAGE in the ischemic hind limb and the role of RAGE signaling in this cell type. Methods and Results Using a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. Although wild-type satellite cells increased tumor necrosis factor-α and monocyte chemoattractant protein-1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand high-mobility group box 1. Furthermore, encapsulated wild-type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification, but RAGE knockout satellite cells provided no improvement over empty capsules. Conclusions Thus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions.

SUBMITTER: Hansen L

PROVIDER: S-EPMC8751830 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice.

Project description:Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, N?-(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth.

| S-EPMC5214531 | biostudies-literature

Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene.

Project description:The alternative splicing of pre-mRNAs is a critical mechanism in genomic complexity, disease, and development. Studies of the receptor for advanced glycation end-products (RAGE) indicate that this gene undergoes a variety of splice events in humans. However, no studies have extensively analyzed the tissue distribution in other species or compared evolutionary differences of RAGE isoforms. Because the majority of studies probing RAGE function have been performed in murine models, we therefore performed studies to identify and characterize the splice variants of the murine RAGE gene, and we compared these to human isoforms. Here, using mouse tissues, we identified numerous splice variants including changes in the extracellular domain or the removal of the transmembrane and cytoplasmic domains, which produce soluble splice isoforms. Comparison of splice variants between humans and mice revealed homologous regions in the RAGE gene that undergo splicing as well as key species-specific mechanisms of splicing. Further analysis of tissue splice variant distribution in mice revealed major differences between lung, kidney, heart, and brain. To probe the potential impact of disease-like pathological states, we studied diabetic mice and report that RAGE splice variation changed dramatically, resulting in an increase in production of soluble RAGE (sRAGE) splice variants, which were not associated with detectable levels of sRAGE in murine plasma. In conclusion, we have determined that the murine RAGE gene undergoes extensive splicing with distinct splice isoforms being uniquely distributed in different tissues. These differences in RAGE splicing in both physiological and pathogenic states further expand our understanding of the biological repertoire of this receptor in health and disease.

| S-EPMC2698653 | biostudies-literature

The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs.

Project description:Diabetes-induced hyperglycemia increases the extracellular concentration of methylglyoxal. Methylglyoxal-derived hydroimidazolones (MG-H) form advanced glycation end products (AGEs) that accumulate in the serum of diabetic patients. The binding of hydroimidozolones to the receptor for AGEs (RAGE) results in long-term complications of diabetes typified by vascular and neuronal injury. Here we show that binding of methylglyoxal-modified albumin to RAGE results in signal transduction. Chemically synthesized peptides containing hydroimidozolones bind specifically to the V domain of RAGE with nanomolar affinity. The solution structure of an MG-H1-V domain complex revealed that the hydroimidazolone moiety forms multiple contacts with a positively charged surface on the V domain. The high affinity and specificity of hydroimidozolones binding to the V domain of RAGE suggest that they are the primary AGE structures that give rise to AGEs-RAGE pathologies.

| S-EPMC4038343 | biostudies-literature

The anti-tumor effects of evodiamine on oral squamous cell carcinoma (OSCC) through regulating advanced glycation end products (AGE) / receptor for advanced glycation end products (RAGE) pathway.

Project description:Evodiamine (EVO) is emerging as a novel anti-tumor drug, which is involved in the inhibition of cell proliferation and apoptosis. High-Mobility Group Box 1 (HMGB1)/RAGE is involved in invasive behavior of OSCC cells and angiogenesis. In this study, we evaluated the potential of EVO in OSCC in vitro and in vivo. We found that RAGE silencing suppressed HSC-4 cell proliferation and invasion, and tube formation of HUVEC. EVO showed marked inhibitory effects on the malignant behaviors of HSC-4 cells in a dose-dependent manner. Further experiments revealed that the RAGE overexpression was able to markedly block the effects of EVO on cell proliferation and invasion, and tube formation. By analyzing the expression of High-Mobility Group Box 1 (HMGB1) and RAGE in HSC-4 cells, the result showed that EVO slightly reduced HMBG1 levels and dramatically decreased RAGE levels, while RAGE overexpression did have no marked influences on HMBG1 levels. The anti-tumor effects of EVO were further confirmed in mouse oral squamous cell carcinoma xenograft models. Remarkable anti-tumor effects of EVO were also demonstrated, as presented by reduced tumor size and levels of HMBG1 and RAGE in tumor tissue of mouse oral squamous cell carcinoma xenograft models. The results demonstrated that EVO has a direct binding effect on HMGB1, but it may be involved in degrading the protein. More importantly, it can reduce the activity of RAGE pathway by affecting the binding between HMBG1 and RAGE. To conclude, EVO inhibited proliferation, invasion and angiogenesis of OSCC through affecting the downstream signal transduction system of AGE/RAGE by targeting RAGE.

| S-EPMC8806666 | biostudies-literature

Characterization of ?X I-Domain Binding to Receptors for Advanced Glycation End Products (RAGE).

Project description:The ?2 integrins are cell surface transmembrane proteins regulating leukocyte functions, such as adhesion and migration. Two members of ?2 integrin, ?M?2 and ?X?2, share the leukocyte distribution profile and integrin ?X?2 is involved in antigen presentation in dendritic cells and transendothelial migration of monocytes and macrophages to atherosclerotic lesions. Receptor for advanced glycation end products (RAGE), a member of cell adhesion molecules, plays an important role in chronic inflammation and atherosclerosis. Although RAGE and ?X?2 play an important role in inflammatory response and the pathogenesis of atherosclerosis, the nature of their interaction and structure involved in the binding remain poorly defined. In this study, using I-domain as a ligand binding motif of ?X?2, we characterize the binding nature and the interacting moieties of ?X I-domain and RAGE. Their binding requires divalent cations (Mg2+ and Mn2+) and shows an affinity on the sub-micro molar level: the dissociation constant of ?X I-domains binding to RAGE being 0.49 ?M. Furthermore, the ?X I-domains recognize the V-domain, but not the C1 and C2-domains of RAGE. The acidic amino acid substitutions on the ligand binding site of ?X I-domain significantly reduce the I-domain binding activity to soluble RAGE and the alanine substitutions of basic amino acids on the flat surface of the V-domain prevent the V-domain binding to ?X I-domain. In conclusion, the main mechanism of ?X I-domain binding to RAGE is a charge interaction, in which the acidic moieties of ?X I-domains, including E244, and D249, recognize the basic residues on the RAGE V-domain encompassing K39, K43, K44, R104, and K107.

| S-EPMC5463044 | biostudies-literature

Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis.

Project description:Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood-brain barrier (BBB) and by increasing the receptor for advanced glycation end product (RAGE) expression in the brain, which causes glial cell activation, leading to cognitive impairment. To test our hypothesis, 60-day-old Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a control group and were treated with a RAGE-specific inhibitor (FPS-ZM1) in saline. The rats also received ceftriaxone 100 mg/kg intraperitoneally, bid, and fluid replacements. Experimental pneumococcal meningitis triggered BBB disruption after meningitis induction, and FPS-ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF-α and IL-1β in the prefrontal cortex (PFC); high expression levels of RAGE, amyloid-β (Aβ1-42), and microglial cell activation in the PFC and hippocampus; and memory impairment, as evaluated by the open-field, novel object recognition task and Morris water maze behavioral tasks. Targeted RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ1-42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats. The sequence of events generated by pneumococcal meningitis can persist long after recovery, triggering neurocognitive decline; however, RAGE blocker attenuated the development of brain inflammation and cognitive impairment in experimental meningitis.

| S-EPMC8116405 | biostudies-literature

The Receptor for Advanced Glycation End Products (RAGE) Is Associated with Persistent Atrial Fibrillation.

Project description:ObjectiveUpregulation of the receptor for advanced glycation end products (RAGE) has been proposed as a pathophysiological mechanism underlying the development of atrial fibrillation (AF). We sought to investigate if soluble RAGE levels are associated with AF in Caucasian patients.MethodsPatients (n = 587) were prospectively recruited and serum levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) measured. The patients included 527 with sinus rhythm, 32 with persistent AF (duration >7 days, n = 32) and 28 with paroxysmal AF (duration <7 days, n = 28).ResultsPatients with AF were older and had a greater prevalence of heart failure than patients in sinus rhythm. Circulating RAGE levels were higher in patients with persistent AF [median sRAGE 1190 (724-2041) pg/ml and median esRAGE 452 (288-932) pg/ml] compared with paroxysmal AF [sRAGE 799 (583-1033) pg/ml and esRAGE 279 (201-433) pg/ml, p ≤ 0.01] or sinus rhythm [sRAGE 782 (576-1039) pg/ml and esRAGE 289 (192-412) pg/ml, p < 0.001]. In multivariable logistic regression analysis, independent predictors of persistent AF were age, heart failure, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% confidence interval (CI) 1.0-1.1, p = 0.001] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.1-1.4, p < 0.001]. Heart failure and age were the only independent predictors of paroxysmal AF. In AF patients, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% CI 1.1-1.2, p = 0.007] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.0-1.5, p = 0.017] independently predicted persistent compared with paroxysmal AF.ConclusionsSoluble RAGE is elevated in Caucasian patients with AF, and both sRAGE and esRAGE predict the presence of persistent AF.

| S-EPMC5023161 | biostudies-literature

Receptor for advanced glycation end products (RAGE) on iNKT cells mediates lung ischemia-reperfusion injury.

Project description:Activation of invariant natural killer T (iNKT) cells and signaling through receptor for advanced glycation end products (RAGE) are known to independently mediate lung ischemia-reperfusion (IR) injury. This study tests the hypothesis that activation of RAGE specifically on iNKT cells via alveolar macrophage-produced high mobility group box 1 (HMGB1) is critical for the initiation of lung IR injury. A murine in vivo hilar clamp model was utilized, which demonstrated that RAGE(-/-) mice were significantly protected from IR injury. Treatment of WT mice with soluble RAGE (a decoy receptor), or anti-HMGB1 antibody, attenuated lung IR injury and inflammation, whereas treatment with recombinant HMGB1 enhanced IR injury in WT mice but not RAGE(-/-) mice. Importantly, lung dysfunction, cytokine production and neutrophil infiltration were significantly attenuated after IR in J?18(-/-) mice reconstituted with RAGE(-/-) iNKT cells (versus WT iNKT cells). In vitro studies demonstrated that, after hypoxia-reoxygenation, alveolar macrophage-derived HMGB1 augmented IL-17 production from iNKT cells in a RAGE-dependent manner. These results suggest that HMGB1-mediated RAGE activation on iNKT cells is critical for initiation of lung IR injury and that a crosstalk between macrophages and iNKT cells via the HMGB1/RAGE axis mediates IL-17 production by iNKT cells causing neutrophil infiltration and lung IR injury.

| S-EPMC3776006 | biostudies-literature

Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases.

Project description:It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE-/- animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE-/- mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE-/- animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.

| S-EPMC6651235 | biostudies-literature

Advanced Glycation End Products and Receptor (RAGE) Promote Wound Healing of Human Corneal Epithelial Cells.

Project description:Purpose:We used a human corneal epithelial cell (HCE) line to determine the involvement of the advanced glycation end products (AGEs) / receptor for AGEs (RAGE) couple in corneal epithelium wound healing. Methods:After wounding, HCE cells were exposed to two major RAGE ligands (HMGB1 and AGEs), and wound healing was evaluated using the in vitro scratch assay. Following wound healing, the HCE cells were used to study the influence of the RAGE ligands on HCE proliferation, invasion, and migration. Activation of the nuclear factor (NF)-κB signaling pathway by the AGEs/RAGE couple was tested using a luciferase reporter assay. Functional transcriptional regulation by this pathway was confirmed by quantification of expression of the connexin 43 target gene. For each experiment, specific RAGE involvement was confirmed by small interfering RNA treatments. Results:AGEs treatment at a dose of 100 µg/mL significantly improved the wound healing process in a RAGE-dependent manner by promoting cell migration, whereas HMGB1 had no effect. No significant influence of the AGEs/RAGE couple was observed on cell proliferation and invasion. However, this treatment induced an early activation of the NF-κB pathway and positively regulated the expression of the target gene, connexin 43, at both the mRNA and protein levels. Conclusions:Our results demonstrate that the RAGE pathway is activated by AGEs treatment and is involved in the promotion of corneal epithelial wound healing. This positive action is observed only during the early stages of wound healing, as illustrated by the quick activation of the NF-κB pathway and induction of connexin 43 expression.

| S-EPMC7401750 | biostudies-literature

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