Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE.
Marie-Paule Wautier,O. Chappey,Stefano Corda,David M. Stern,Ann Marie Schmidt,Jean-Luc Wautier +5 more
TLDR
Findings underscore a central role of NADPH oxidase in AGE-RAGE-mediated generation of ROS and provide a mechanism for altered gene expression in A GE-related disorders.Abstract:
Engagement of the receptor for advanced glycation end products (RAGE) by products of nonenzymatic glycation/oxidation triggers the generation of reactive oxygen species (ROS), thereby altering gene expression. Because dissection of the precise events by which ROS are generated via RAGE is relevant to the pathogenesis of complications in AGE-related disorders, such as diabetes and renal failure, we tested the hypothesis that activation of NADPH oxidase contributed, at least in part, to enhancing oxidant stress via RAGE. Here we show that incubation of human endothelial cells with AGEs on the surface of diabetic red blood cells, or specific AGEs, (carboxymethyl)lysine (CML)-modified adducts, prompted intracellular generation of hydrogen peroxide, cell surface expression of vascular cell adhesion molecule-1, and generation of tissue factor in a manner suppressed by treatment with diphenyliodonium, but not by inhibitors of nitric oxide. Consistent with an important role for NADPH oxidase, although macrophages derived from wild-type mice expressed enhanced levels of tissue factor upon stimulation with AGE, macrophages derived from mice deficient in a central subunit of NADPH oxidase, gp91phox, failed to display enhanced tissue factor in the presence of AGE. These findings underscore a central role of NADPH oxidase in AGE-RAGE-mediated generation of ROS and provide a mechanism for altered gene expression in AGE-related disorders.read more
Citations
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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction Molecular and Pathophysiological Mechanisms
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Understanding RAGE, the receptor for advanced glycation end products
Angelika Bierhaus,Per M. Humpert,Michael Morcos,Thoralf Wendt,Triantafyllos Chavakis,Bernd Arnold,David M. Stern,Peter P. Nawroth +7 more
TL;DR: Administration of the receptor decoy, sRAGE, is likely to sequester ligands, thereby preventing their interaction with other receptors in addition to RAGE, suggesting that, just as RAGE is a multiligand receptor, its ligands are also likely to recognize several receptors in mediating their biologic effects.
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RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
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RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.
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TL;DR: It is reported here that receptor for AGE (RAGE) is a central cell surface receptor for EN-RAGE (extracellular newly identified RAGE-binding protein) and related members of the S100/calgranulin superfamily.
Journal ArticleDOI
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Journal ArticleDOI
Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins.
M. Neeper,Ann Marie Schmidt,J. Brett,Shi Du Yan,Feng Wang,Y.-C. E. Pan,Keith O. Elliston,David M. Stern,Alan Shaw +8 more
TL;DR: RAGE is a new member of the immunoglobulin superfamily of cell surface molecules and shares significant homology with MUC 18, NCAM, and the cytoplasmic domain of CD20 and could potentially mediate cellular effects of this class of glycosylated proteins.