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Inverse Relationship between Soluble RAGE and Risk for Bronchopulmonary Dysplasia.
Benjamin JT, van der Meer R, Slaughter JC, Steele S, Plosa EJ, Sucre JM, Moore PE, Aschner JL, Blackwell TS, Young LR
(2018) Am J Respir Crit Care Med 197: 1083-1086
MeSH Terms: Biomarkers, Bronchopulmonary Dysplasia, California, Female, Gestational Age, Humans, Infant, Low Birth Weight, Infant, Newborn, Infant, Premature, Male, Receptor for Advanced Glycation End Products, Risk Factors
Added March 21, 2018
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12 MeSH Terms
RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis.
Noto MJ, Becker KW, Boyd KL, Schmidt AM, Skaar EP
(2017) Infect Immun 85:
MeSH Terms: Acinetobacter Infections, Acinetobacter baumannii, Animals, Disease Models, Animal, Female, Immunity, Innate, Interleukin-10, Kaplan-Meier Estimate, Leukocyte Count, Mice, Mice, Knockout, Receptor for Advanced Glycation End Products, Sepsis, Severity of Illness Index, Signal Transduction
Show Abstract · Added April 8, 2017
The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor capable of recognizing multiple pathogen-associated and danger-associated molecular patterns that contributes to the initiation and potentiation of inflammation in many disease processes. During infection, RAGE functions to either exacerbate disease severity or enhance pathogen clearance depending on the pathogen studied. is an opportunistic human pathogen capable of causing severe infections, including pneumonia and sepsis, in impaired hosts. The role of RAGE signaling in response to opportunistic bacterial infections is largely unknown. In murine models of pneumonia, RAGE signaling alters neither inflammation nor bacterial clearance. In contrast, RAGE mice systemically infected with exhibit increased survival and reduced bacterial burdens in the liver and spleen. The increased survival of RAGE mice is associated with increased circulating levels of the anti-inflammatory cytokine interleukin-10 (IL-10). Neutralization of IL-10 in RAGE mice results in decreased survival during systemic infection that mirrors that of wild-type (WT) mice, and exogenous IL-10 administration to WT mice enhances survival in this model. These findings demonstrate the role for RAGE-dependent IL-10 suppression as a key modulator of mortality from Gram-negative sepsis.
Copyright © 2017 American Society for Microbiology.
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15 MeSH Terms
Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts.
Guo L, Chen Z, Amarnath V, Yancey PG, Van Lenten BJ, Savage JR, Fazio S, Linton MF, Davies SS
(2015) Antioxid Redox Signal 22: 1633-45
MeSH Terms: Aldehydes, Animals, Humans, Inflammation, Lipids, Macrophages, Male, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Phosphatidylethanolamines, Prostaglandins E, Pyrrolidines, Receptor for Advanced Glycation End Products
Show Abstract · Added October 8, 2015
AIMS - Increased lipid peroxidation occurs in many conditions associated with inflammation. Because lipid peroxidation produces lipid aldehydes that can induce inflammatory responses through unknown mechanisms, elucidating these mechanisms may lead to development of better treatments for inflammatory diseases. We recently demonstrated that exposure of cultured cells to lipid aldehydes such as isolevuglandins (IsoLG) results in the modification of phosphatidylethanolamine (PE). We therefore sought to determine (i) whether PE modification by isolevuglandins (IsoLG-PE) occurred in vivo, (ii) whether IsoLG-PE stimulated the inflammatory responses of macrophages, and (iii) the identity of receptors mediating the inflammatory effects of IsoLG-PE.
RESULTS - IsoLG-PE levels were elevated in plasma of patients with familial hypercholesterolemia and in the livers of mice fed a high-fat diet to induce obesity and hepatosteatosis. IsoLG-PE potently stimulated nuclear factor kappa B (NFκB) activation and expression of inflammatory cytokines in macrophages. The effects of IsoLG-PE were blocked by the soluble form of the receptor for advanced glycation endproducts (sRAGE) and by RAGE antagonists. Furthermore, macrophages derived from the bone marrow of Ager null mice failed to express inflammatory cytokines in response to IsoLG-PE to the same extent as macrophages from wild-type mice.
INNOVATION - These studies are the first to identify IsoLG-PE as a mediator of macrophage activation and a specific receptor, RAGE, which mediates its biological effects.
CONCLUSION - PE modification by IsoLG forms RAGE ligands that activate macrophages, so that the increased IsoLG-PE generated by high circulating cholesterol levels or high-fat diet may play a role in the inflammation associated with these conditions.
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14 MeSH Terms
Ascorbate reverses high glucose- and RAGE-induced leak of the endothelial permeability barrier.
Meredith ME, Qu ZC, May JM
(2014) Biochem Biophys Res Commun 445: 30-5
MeSH Terms: Acetylcysteine, Animals, Antioxidants, Ascorbic Acid, Benzamides, Cell Line, Cell Membrane Permeability, Cells, Cultured, Chromans, Cyclic N-Oxides, Dithiothreitol, Dose-Response Relationship, Drug, Endothelial Cells, Glucose, Glycation End Products, Advanced, HMGB1 Protein, Human Umbilical Vein Endothelial Cells, Humans, Mice, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Serum Albumin, Bovine, Spin Labels
Show Abstract · Added May 27, 2014
High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose-induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5mM glucose. Acute loading of the cells for 30-60 min with ascorbate before the permeability assay prevented the high glucose-induced increase in permeability and decreased basal permeability at 5mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose-induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant.
Copyright © 2014 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas.
Pan Z, Grizzle W, Hameed O
(2013) Am J Clin Pathol 140: 410-8
MeSH Terms: Antigens, Neoplasm, Biomarkers, Tumor, Cadherins, Carbonic Anhydrase IX, Carbonic Anhydrases, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, PAX2 Transcription Factor, PAX8 Transcription Factor, Paired Box Transcription Factors, Receptor for Advanced Glycation End Products
Show Abstract · Added March 7, 2014
OBJECTIVES - To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases.
METHODS - Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8).
RESULTS - There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases.
CONCLUSIONS - Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs.
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12 MeSH Terms
α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction.
Inman DM, Lambert WS, Calkins DJ, Horner PJ
(2013) PLoS One 8: e65389
MeSH Terms: Administration, Oral, Animals, Antioxidants, Axons, Cell Death, DNA Damage, Dietary Supplements, Drug Evaluation, Preclinical, Gene Expression, Glaucoma, Intraocular Pressure, Lipid Peroxidation, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Nerve Degeneration, Nitric Oxide Synthase Type II, Oxidation-Reduction, Oxidative Stress, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Retina, Retinal Ganglion Cells, Thioctic Acid, Treatment Outcome, Up-Regulation
Show Abstract · Added May 27, 2014
Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant α-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma.
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26 MeSH Terms
Stable RAGE-heparan sulfate complexes are essential for signal transduction.
Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD
(2013) ACS Chem Biol 8: 1611-20
MeSH Terms: Coordination Complexes, Dimerization, Drug Stability, Endothelial Cells, Heparitin Sulfate, Humans, Models, Molecular, Receptor for Advanced Glycation End Products, Signal Transduction, X-Ray Diffraction
Show Abstract · Added March 7, 2014
RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage-associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erk1/2 phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value.
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10 MeSH Terms
Critical role for the advanced glycation end-products receptor in pulmonary arterial hypertension etiology.
Meloche J, Courchesne A, Barrier M, Carter S, Bisserier M, Paulin R, Lauzon-Joset JF, Breuils-Bonnet S, Tremblay É, Biardel S, Racine C, Courture C, Bonnet P, Majka SM, Deshaies Y, Picard F, Provencher S, Bonnet S
(2013) J Am Heart Assoc 2: e005157
MeSH Terms: Adult, Aged, Animals, Apoptosis, Arterial Pressure, Bone Morphogenetic Protein Receptors, Type II, Case-Control Studies, Cell Proliferation, Cells, Cultured, Disease Models, Animal, Familial Primary Pulmonary Hypertension, Female, Glycation End Products, Advanced, Humans, Hypertension, Pulmonary, Hypertrophy, Right Ventricular, Hypoxia, Indoles, Male, Middle Aged, Monocrotaline, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Pulmonary Artery, Pyrroles, RNA Interference, Rats, Rats, Sprague-Dawley, Receptor for Advanced Glycation End Products, Receptors, Immunologic, S100 Proteins, STAT3 Transcription Factor, Signal Transduction, Transfection, Up-Regulation
Show Abstract · Added August 4, 2015
BACKGROUND - Pulmonary arterial hypertension (PAH) is a vasculopathy characterized by enhanced pulmonary artery smooth muscle cell (PASMC) proliferation and suppressed apoptosis. This results in both increase in pulmonary arterial pressure and pulmonary vascular resistance. Recent studies have shown the implication of the signal transducer and activator of transcription 3 (STAT3)/bone morphogenetic protein receptor 2 (BMPR2)/peroxisome proliferator-activated receptor gamma (PPARγ) in PAH. STAT3 activation induces BMPR2 downregulation, decreasing PPARγ, which both contribute to the proproliferative and antiapoptotic phenotype seen in PAH. In chondrocytes, activation of this axis has been attributed to the advanced glycation end-products receptor (RAGE). As RAGE is one of the most upregulated proteins in PAH patients' lungs and a strong STAT3 activator, we hypothesized that by activating STAT3, RAGE induces BMPR2 and PPARγ downregulation, promoting PAH-PASMC proliferation and resistance to apoptosis.
METHODS AND RESULTS - In vitro, using PASMCs isolated from PAH and healthy patients, we demonstrated that RAGE is overexpressed in PAH-PASMC (6-fold increase), thus inducing STAT3 activation (from 10% to 40% positive cells) and decrease in BMPR2 and PPARγ levels (>50% decrease). Pharmacological activation of RAGE in control cells by S100A4 recapitulates the PAH phenotype (increasing RAGE by 6-fold, thus activating STAT3 and decreasing BMPR2 and PPARγ). In both conditions, this phenotype is totally reversed on RAGE inhibition. In vivo, RAGE inhibition in monocrotaline- and Sugen-induced PAH demonstrates therapeutic effects characterized by PA pressure and right ventricular hypertrophy decrease (control rats have an mPAP around 15 mm Hg, PAH rats have an mPAP >40 mm Hg, and with RAGE inhibition, mPAP decreases to 20 and 28 mm Hg, respectively, in MCT and Sugen models). This was associated with significant improvement in lung perfusion and vascular remodeling due to decrease in proliferation (>50% decrease) and BMPR2/PPARγ axis restoration (increased by ≥60%).
CONCLUSION - We have demonstrated the implications of RAGE in PAH etiology. Thus, RAGE constitutes a new attractive therapeutic target for PAH.
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36 MeSH Terms
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.
Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ, Schmidt AM
(2012) J Exp Med 209: 2339-50
MeSH Terms: Animals, Cell Line, Tumor, Cyclin D1, Female, Humans, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle, Smooth, Vascular, Neoplasms, Proto-Oncogene Proteins c-akt, Rats, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Recombinant Proteins, Signal Transduction
Show Abstract · Added March 12, 2014
The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
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18 MeSH Terms
Structural basis for ligand recognition and activation of RAGE.
Koch M, Chitayat S, Dattilo BM, Schiefner A, Diez J, Chazin WJ, Fritz G
(2010) Structure 18: 1342-52
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, Humans, Hydrogen-Ion Concentration, Kinetics, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Nerve Growth Factors, Protein Binding, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor for Advanced Glycation End Products, Receptors, Immunologic, S100 Calcium Binding Protein beta Subunit, S100 Proteins, Sequence Homology, Amino Acid
Show Abstract · Added March 12, 2014
The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling events upon binding of a variety of ligands, such as glycated proteins, amyloid-β, HMGB1, and S100 proteins. The X-ray crystal structure of the VC1 ligand-binding region of the human RAGE ectodomain was determined at 1.85 Å resolution. The VC1 ligand-binding surface was mapped onto the structure from titrations with S100B monitored by heteronuclear NMR spectroscopy. These NMR chemical shift perturbations were used as input for restrained docking calculations to generate a model for the VC1-S100B complex. Together, the arrangement of VC1 molecules in the crystal and complementary biochemical studies suggest a role for self-association in RAGE function. Our results enhance understanding of the functional outcomes of S100 protein binding to RAGE and provide insight into mechanistic models for how the receptor is activated.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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21 MeSH Terms