Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses. RAGE also functions as a signal transduction receptor for amyloid beta peptide, known to accumulate in Alzheimer disease in both affected brain parenchyma and cerebral vasculature. Interaction of RAGE with these ligands enhances receptor expression and initiates a positive feedback loop whereby receptor occupancy triggers increased RAGE expression, thereby perpetuating another wave of cellular activation. Sustained expression of RAGE by critical target cells, including endothelium, smooth muscle cells, mononuclear phagocytes, and neurons, in proximity to these ligands, sets the stage for chronic cellular activation and tissue damage. In a model of accelerated atherosclerosis associated with diabetes in genetically manipulated mice, blockade of cell surface RAGE by infusion of a soluble, truncated form of the receptor completely suppressed enhanced formation of vascular lesions. Amelioration of atherosclerosis in these diabetic/atherosclerotic animals by soluble RAGE occurred in the absence of changes in plasma lipids or glycemia, emphasizing the contribution of a lipid- and glycemia-independent mechanism(s) to atherogenesis, which we postulate to be interaction of RAGE with its ligands. Future studies using mice in which RAGE expression has been genetically manipulated and with selective low molecular weight RAGE inhibitors will be required to definitively assign a critical role for RAGE activation in diabetic vasculopathy. However, sustained receptor expression in a microenvironment with a plethora of ligand makes possible prolonged receptor stimulation, suggesting that interaction of cellular RAGE with its ligands could be a factor contributing to a range of important chronic disorders.
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PMID:Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. 1008 70

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.
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PMID:Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. 1083 Sep 43

Receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose repertoire of ligands includes advanced glycation end products (AGEs), amyloid fibrils, amphoterins and S100/calgranulins. The overlapping distribution of these ligands and cells overexpressing RAGE results in sustained receptor expression which is magnified via the apparent capacity of ligands to upregulate the receptor. We hypothesize that RAGE-ligand interaction is a propagation factor in a range of chronic disorders, based on the enhanced accumulation of the ligands in diseased tissues. For example, increased levels of AGEs in diabetes and renal insufficiency, amyloid fibrils in Alzheimer's disease brain, amphoterin in tumors and S100/calgranulins at sites of inflammation have been identified. The engagement of RAGE by its ligands can be considered the 'first hit' in a two-stage model, in which the second phase of cellular perturbation is mediated by superimposed accumulation of modified lipoproteins (in atherosclerosis), invading bacterial pathogens, ischemic stress and other factors. Taken together, these 'two hits' eventuate in a cellular response with a propensity towards tissue destruction rather than resolution of the offending pathogenic stimulus. Experimental data are cited regarding this hypothesis, though further studies will be required, especially with selective low molecular weight inhibitors of RAGE and RAGE knockout mice, to obtain additional proof in support of our concept.
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PMID:The biology of the receptor for advanced glycation end products and its ligands. 1110 54

Adhesion of circulating cells to the vascular endothelium is an early step in the development of atherosclerosis. Diabetic patients have a 2-4 fold increased risk for the development of atherosclerosis. Expression of adhesion molecules is increased in diabetes. These molecules may contribute to accelerated atherosclerosis in diabetes. Three main groups of adhesion molecules have been identified: integrins, selectins and members of the immunoglobulin superfamily. The modulation of expression and activity of adhesion molecules may play an important role in the prevention and treatment of atherosclerosis. This article summarises the characteristics and the role of these molecules in atherosclerosis and diabetes.
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PMID:[The role of adhesion molecules in atherosclerosis and diabetes mellitus]. 1112 80

RAGE is a multiligand member of the immunoglobulin superfamily of cell surface molecules whose properties extend the paradigm of ligand-receptor interactions. The receptor recognizes families of ligands with diverse structural features, such as advanced glycation endproducts (AGEs), amyloidogenic peptides/polypeptides, amphoterins, and S100/calgranulins rather than individual species. Engagement of RAGE by its ligands upregulates the receptor and initiates a cycle of sustained cellular perturbation; increased levels of RAGE on the cell surface make it an ideal target for subsequent ligand interactions and for propagating cellular dysfunction. At this time, the only means known to break this apparently vicious cycle appears to be blocking access to RAGE or removing the ligands. Taken together, these data suggest that RAGE has the potential to function as a progression factor in a range of disorders (AGEs are relevant to diabetes and other settings of oxidant stress, amyloidogenic peptides are relevant to amyloidoses, S100/calgranulins are relevant to inflammatory disorders, etc.) in which its ligands accumulate. The chronic juxtaposition of ligand and receptor triggers sustained cellular perturbation favoring mechanisms eventuating in tissue injury rather than those that would restore homeostasis.
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PMID:RAGE: a multiligand receptor contributing to the cellular response in diabetic vasculopathy and inflammation. 1112 4

Three genes that encode related immunoglobulin superfamily molecules have recently been mapped to human chromosome 15 in the region q22.3-q23 and to the syntenic region on mouse chromosome 9. These genes presumably derived from gene duplications, and they are highly similar to Deleted in Colorectal Cancer (DCC), which functions as an axon guidance molecule during development of the nervous system. To find out whether additional genes of this class were present in a chromosomal cluster, we produced a comparative physical map within the region of synteny between mouse chromosome 9 and human chromosome 15. This interval overlaps the critical region for the fourth genetic locus for Bardet-Biedl syndrome (BBS4) in humans. Bardet-Biedl syndrome (OMIM 600374) is characterized by poly/syn/brachydactyly, retinal degeneration, hypogonadism, mental retardation, obesity, diabetes, and kidney abnormalities. A detailed map of this locus will help to identify candidate genes for this disorder.
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PMID:09/15: Comparative genomics of a conserved chromosomal region associated with a complex human phenotype. 1131 7

A variety of recently discovered glycoproteins have been implicated in cell-cell interactions that are critical for normal hemostasis, immune surveillance, and vascular wall integrity. These cell adhesion molecules (CAM) are known to mediate blood cell (leukocyte, platelet)-endothelial cell interactions that can occur in all segments of the microvasculature under certain physiological (eg, hemostasis) and pathological (eg, inflammation) conditions. The multistep process of leukocyte recruitment illustrates how the coordinated and regulated expression of structurally and functionally distinct families of CAM can elicit a highly reproducible vascular response to inflammation. Selectins mediate the initial, low-affinity leukocyte-endothelial cell interaction that is manifested as leukocyte rolling. This transient binding results in further leukocyte activation and subsequent firm adhesion and transendothelial migration of leukocytes, both of which are mediated by interactions between members of the integrin and immunoglobulin superfamily of CAM. This CAM-regulated process of leukocyte recruitment often results in endothelial cell dysfunction, which can be manifested as either impaired endothelium-dependent vasorelaxation in arterioles, excess fluid filtration in capillaries, and enhanced protein extravasation in venules. Consequently, CAM have been implicated in a variety of vascular disorders (eg, ischemia/reperfusion, atherosclerosis, allograft dysfunction, and vasculitis) and an enhanced expression of these CAM has been invoked to explain the exaggerated microvascular dysfunction associated with some of the risk factors (hypertension, hypercholesterolemia, diabetes) for cardiovascular disease. Monoclonal antibodies and genetically engineered mice have proven to be valuable tools for defining the contribution of CAM to disease progression and provide hope for new diagnostic and therapeutic strategies for cardiovascular diseases.
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PMID:Adhesion molecules and their role in vascular disease. 1141 65

Receptor for AGE (RAGE), a member of the immunoglobulin superfamily, was first identified as a specific cell surface interaction site for Advanced Glycation Endproducts, or AGEs. AGEs, the products of nonenzymatic glycation/oxidation of proteins/lipids, accumulate in natural aging and disorders such as diabetes, renal failure and amyloidoses. Interaction of AGEs with RAGE has been linked to chronic inflammatory and vascular dysfunction that characterizes the chronic complications of these disorders. Recent studies have indicated that RAGE is a multiligand receptor, serving as a specific cell surface, signal transducing receptor for amphoterin, a molecule with implications for neurite outgrowth in neuronal development and in tumor cell proliferation and spread. RAGE is also a receptor for amyloid-beta peptide, whose interaction with neuronal and microglial RAGE within the CNS is linked to sustained inflammation and neuronal toxicity and cell death. RAGE also serves as a signal-transducing receptor for EN-RAGEs, and related members of the S100/calgranulin family of proinflammatory cytokines; consequences of this interaction include initiation and propagation of inflammatory responses. Consistent with an important role for ligand-RAGE interaction in these settings, blockade of RAGE suppresses chronic cellular activation and dysfunction in murine models of diabetic complications, inflammation and tumor proliferation and metastasis. Taken together, an new paradigm is emerging which links RAGE, a gene encoded within the Major Histocompatibility Complex (MHC) Class III regions, to central host response mechanisms in homeostasis and chronic disease.
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PMID:Receptor for age (RAGE) is a gene within the major histocompatibility class III region: implications for host response mechanisms in homeostasis and chronic disease. 1157 72

RAGE (receptor for advanced glycation end products) is a multiligand cell surface molecule of the immunoglobulin superfamily. It was originally described as a receptor for protein adducts formed by glycoxidation (AGEs) that accumulate in diseases such as diabetes and renal failure. Performing RT-PCR and Western blot analysis we intended to determine RAGE expression in the human colon adenocarcinoma cell line Caco-2. Moreover, Caco-2 cells were incubated in the presence of AGEs. Since RAGE ligation triggers the p21(ras) signal transduction pathway the activation state of p44/42 (ERK1/2) MAP kinases was determined. Here we demonstrate for the first time that Caco-2 cells express RAGE and that administration of the food-derived casein-linked AGE N(epsilon)-(carboxymethyl)lysine (Cas-CML) results in Caco-2 p44/42 (ERK1/2) MAP kinase activation.
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PMID:RAGE expression and AGE-induced MAP kinase activation in Caco-2 cells. 1170 25

S100A12 is a member of the S100 subfamily of EF-hand calcium-binding proteins; it has been shown to be one of the ligands of the 'receptor for advanced glycation end products' (RAGE) that belongs to the immunoglobulin superfamily and is involved in diabetes, Alzheimer's disease, inflammation and tumour invasion. The structure of the dimeric form of native S100A12 from human granulocytes in the presence of calcium in space group R3 has previously been reported. Here, the structure of a second crystal form in space group P2(1) (unit-cell parameters a = 53.9, b = 100.5, c = 112.7A, beta = 94.6 degrees) solved at 2.7A resolution by molecular replacement using the R3 structure as a search model is reported. Like most S100 proteins, S100A12 is a dimer. However, in the P2(1) crystal form dimers of S100A12 are arranged in a spherical hexameric assembly with an external diameter of about 55 A stabilized by calcium ions bound between adjacent dimers. The putative target-binding sites of S100A12 are located at the outer surface of the hexamer, making it possible for the hexamer to bind several targets. It is proposed that the S100A12 hexameric assembly might interact with three extracellular domains of the receptor, bringing them together into large trimeric assemblies.
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PMID:The structure of S100A12 in a hexameric form and its proposed role in receptor signalling. 1185 25


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