Aminoguanidine inhibits advanced glycation end products formation on beta2-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.
Hou
F F
FF
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Boyce
J
J
Chertow
G M
GM
Kay
J
J
Owen
W F
WF
D000704:Analysis of Variance; D003094:Collagen / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000737:chemistry*; D006031:Glycosylation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D013050:Spectrometry, Fluorescence; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000187:drug effects*
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D001613:beta 2-Microglobulin; D003094:Collagen; D005947:Glucose; C004479:pimagedine