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The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta2microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway. Implications for the pathogenesis of dialysis-related amyloidosis.
Miyata, Toshio Hori, Osamu Zhang, JingHua Yan, Shirley ShiDu Ferran, Luis Iida, Yoshiyasu Schmidt, Ann Marie
Miyata, Toshio
Hori, Osamu
Zhang, JingHua
Yan, Shirley ShiDu
Ferran, Luis
Iida, Yoshiyasu
Schmidt, Ann Marie
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Abstract
An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta2M. We demonstrate here that the interaction of AGE-beta2M with mononuclear phagocytes (MPs), cells important in the pathogenesis of the inflammatory arthropathy of dialysis-related amyloidosis, is mediated by the receptor for AGEs, or RAGE. 125I-AGE-beta2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (Kd approximately 53.5 and approximately 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-beta2M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG. Induction of tumor necrosis factor-alpha (TNF) expression by MPs exposed to AGE-beta2M resulted from engagement of RAGE, as appearances of TNF transcripts and TNF antigen release into culture supernatants were prevented by addition of sRAGE, a process mediated, at least in part, by oxidant stress. AGE-beta2M reduced cytochrome c and the elaboration of TNF by MPs was inhibited by N-acetylcysteine. Consistent with these data, immunohistochemical studies of AGE-laden amyloid deposits of a long-term hemodialysis patient revealed positive staining for RAGE in the MPs infiltrating these lesions. These data indicate that RAGE is a central binding site for AGEs formed in vivo and suggest that AGE-beta2M-MP-RAGE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a process which may ultimately lead to bone and joint destruction.
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This is the published version. Copyright 1996 American Society for Clinical Investigation.
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1996-09-01
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American Society for Clinical Investigation
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Miyata, T., O. Hori, J. Zhang, S. D. Yan, L. Ferran, Y. Iida, and A. M. Schmidt. "The Receptor for Advanced Glycation End Products (RAGE) Is a Central Mediator of the Interaction of AGE-beta2microglobulin with Human Mononuclear Phagocytes via an Oxidant-sensitive Pathway. Implications for the Pathogenesis of Dialysis-related Amyloidosis." Journal of Clinical Investigation J. Clin. Invest. 98.5 (1996): 1088-094. http://dx.doi.org/10.1172/JCI118889.