AMINOGUANIDINE INHIBITS ADVANCED GLYCATION END-PRODUCTS FORMATION ON BETA-2-MICROGLOBULIN

Because advanced glycation end products (AGE)modified beta 2-microglob ulin (AGE-beta 2M) is a dominant constituent of amyloid in dialysis-re lated amyloidosis (DRA), AGE-beta 2M may be directly involved in the p athobiology of DRA. In experimental diabetes mellitus, blocking the fo rmation of AGE prevents AGE-mediated tissue damage. In this study, it is postulated that similar pharmacologic intervention may be beneficia l in DRA. Aminoguanidine, a nucleophilic hydrazine compound that preve nts AGE formation on collagen, may have a similar effect on the advanc ed glycation of beta 2M. To test this hypothesis, beta 2M was incubate d in vitro with 50 or 100 mM D-glucose for 3 wk in the presence and ab sence of incremental concentrations of aminoguanidine. On the basis of enzyme-linked immunosorbent assay and immunoblots using anti-AGE-keyh ole limpet hemocyanin antibody, aminoguanidine inhibited glucose-induc ed N-epsilon-(carboxymethyl)lysine formation on beta 2M. At aminoguani dine-glucose molar ratios of 1:8 to 1:1, 26 to 53% inhibition occurred . Fluorospectrometry examination showed that aminoguanidine also inhib ited the formation of fluorescent AGE on beta 2M in a dose-dependent m anner. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, fluoresce nt product generation was inhibited by 30 to 70%. Furthermore, aminogu anidine suppressed the AGE formation on beta 2M bound to AGE-modified collagen. If aminoguanidine is similarly active in vivo, this compound may be of clinical utility for treating DRA in patients on maintenanc e dialysis.