An important component of amyloid fibrils in dialysis-related amyloidosis is a form of β2microglobulin modified with advanced glycation end products (AGEs) of the Maillard reaction, known as AGE-β2M. We demonstrate here that the interaction of AGE-β2M 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. 125-AGE-β2M bound to immobilized RAGE or to MPs in a specific, dose-dependent manner (K(d) ≃ 53.5 and ≃ 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade. AGE-β2M-mediated monocyte chemotaxis was prevented by excess sRAGE or anti-RAGE IgG. Induction of tumor necrosis factor-α (TNF) expression by MPs exposed to AGE-β2M 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. AGEβ2M 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-β2M-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.
- glycated proteins
- long-term hemodialysis patients
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