The receptor for advanced glycation end products (RAGE) is a central mediator of the interaction of AGE-beta(2)microglobulin with human mononuclear phagocytes via an oxidant-sensitive pathway - Implications for the pathogenesis of dialysis-related amyloidosis

An important component of amyloid fibrils in dialysis-related amyloidosis is a form of beta(2)microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-beta(2)M. We demonstrate here that the interaction of AGE-beta(2)M 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. I-125-AGE-beta(2)M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (K-d approximate to 53.5 and approximate to 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade, AGE-beta(2)M-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-beta(2)M 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 beta(2)M 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-beta(2)M-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.