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 amyloido sis 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 mononucl ear phagocytes (MPs), cells important in the pathogenesis of the infla mmatory arthropathy of dialysis-related amyloidosis, is mediated by th e 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 t o 53.5 and approximate to 81.6 nM, respectively), a process inhibited in the presence of RAGE blockade, AGE-beta(2)M-mediated monocyte chemo taxis was prevented by excess sRAGE or anti-RAGE IgG, Induction of tum or 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 a ddition of sRAGE, a process mediated, at least in part, by oxidant str ess, AGE beta(2)M reduced cytochrome c and the elaboration of TNF by M Ps was inhibited by N-acetylcysteine. Consistent with these data, immu nohistochemical studies of AGE-laden amyloid deposits of a long-term h emodialysis patient revealed positive staining for RAGE in the MPs inf iltrating these lesions. These data indicate that RAGE is a central bi nding site for AGEs formed in vivo and suggest that AGE-beta(2)M-MP-RA GE interaction likely contributes to the initiation of an inflammatory response in amyloid deposits of long-term hemodialysis patients, a pr ocess which may ultimately lead to bone and joint destruction.