ENHANCED CELLULAR OXIDANT STRESS BY THE INTERACTION OF ADVANCED GLYCATION END-PRODUCTS WITH THEIR RECEPTORS BINDING-PROTEINS

Attack by reactive oxygen intermediates, common to many kinds of cell/ tissue injury, has been implicated in the development of diabetic and other vascular diseases. Such oxygen-free radicals can be generated by advanced glycation end products (AGEs), which are nonenzymatically gl ycated and oxidized proteins. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGE (RAGE ) and the lactoferrin-like polypeptide (LF-L), we tested the hypothesi s that AGE ligands tethered to the complex of RAGE and LF-L could indu ce oxidant stress. AGE albumin or AGEs immunoisolated from diabetic pl asma resulted in induction of endothelial cell (EC) oxidant stress, in cluding the generation of thiobarbituric acid reactive substances (TBA RS) and resulted in the activation of NF-kappaB, each of which was blo cked by antibodies to AGE receptor polypeptides and by antioxidants. I nfusion of AGE albumin into normal animals led to the appearance of ma londialdehyde determinants in the vessel wall and increased TBARS in t he tissues, activation of NF-kappaB, and induction of heme oxygenase m RNA. AGE-induced oxidant stress was inhibited by pretreatment of anima ls with either antibodies to the AGE receptor/binding proteins or anti oxidants. These data indicate that interaction of AGEs with cellular t argets, such as ECs, leads to oxidant stress resulting in changes in g ene expression and other cellular properties, potentially contributing to the development of vascular lesions. Further studies will be requi red to dissect whether oxidant stress occurs on the cell surface or at an intracellular locus.