Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin
Department of Medicine, Division of Rheumatology
Analysis of Variance; Collagen; Dose-Response Relationship, Drug; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Glucose; Glycosylation; Glycosylation End Products, Advanced; Guanidines; Humans; Immunoblotting; In Vitro Techniques; Spectrometry, Fluorescence; beta 2-Microglobulin
Because advanced glycation end products (AGE)-modified beta2-microglobulin (AGE-beta2M) is a dominant constituent of amyloid in dialysis-related amyloidosis (DRA), AGE-beta2M may be directly involved in the pathobiology of DRA. In experimental diabetes mellitus, blocking the formation of AGE prevents AGE-mediated tissue damage. In this study, it is postulated that similar pharmacologic intervention may be beneficial in DRA. Aminoguanidine, a nucleophilic hydrazine compound that prevents AGE formation on collagen, may have a similar effect on the advanced glycation of beta2M. To test this hypothesis, beta2M was incubated in vitro with 50 or 100 mM D-glucose for 3 wk in the presence and absence of incremental concentrations of aminoguanidine. On the basis of enzyme-linked immunosorbent assay and immunoblots using anti-AGE-keyhole limpet hemocyanin antibody, aminoguanidine inhibited glucose-induced N(epsilon)-(carboxymethyl)lysine formation on beta2M. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, 26 to 53% inhibition occurred. Fluorospectrometry examination showed that aminoguanidine also inhibited the formation of fluorescent AGE on beta2M in a dose-dependent manner. At aminoguanidine-glucose molar ratios of 1:8 to 1:1, fluorescent product generation was inhibited by 30 to 70%. Furthermore, aminoguanidine suppressed the AGE formation on beta2M 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 maintenance dialysis.
J Am Soc Nephrol. 1998 Feb;9(2):277-83.
Journal of the American Society of Nephrology : JASN
Hou, Fan Fan; Boyce, Joshua; Chertow, Glenn M.; Kay, Jonathan; and Owen, William F. Jr., "Aminoguanidine inhibits advanced glycation end products formation on beta2-microglobulin" (1998). Rheumatology Publications and Presentations. 81.