To investigate the role of the Maillard reaction in the pathogenesis of
diabetic complications, we produced several clones of
monoclonal antibodies against
advanced glycation end products (AGEs) by immunizing mice with AGE-modified
keyhole limpet hemocyanin, and found that one clone (AG-1) of the anti-AGE
antibodies reacted specifically with imidazolones A and B, novel AGEs. Thus, the imidazolones, which are the reaction products of the guanidino group of
arginine with
3-deoxyglucosone (3-DG), a reactive intermediate of the Maillard reaction, were found to be common
epitopes of AGE-modified
proteins produced in vitro. We determined the erythrocyte levels of
imidazolone in diabetic patients using ELISA with the monoclonal anti-
imidazolone antibody. The
imidazolone levels in the erythrocytes of diabetic patients were found to be significantly increased as compared with those of healthy subjects. Then we studied the localization of
imidazolone in the kidneys and aortas obtained from diabetic patients by immunohistochemistry using the antibody. Specific
imidazolone immunoreactivity was detected in nodular lesions and expanded mesangial matrix of glomeruli, and renal arteries in an advanced stage of
diabetic nephropathy, as well as in atherosclerotic lesions of aortas. This study first demonstrates the localization of
imidazolone in the characteristic lesions of
diabetic nephropathy and
atherosclerosis. These results, taken together with a recent demonstration of increased serum 3-DG levels in diabetes, strongly suggest that
imidazolone produced by 3-DG may contribute to the progression of long-term
diabetic complications such as nephropathy and
atherosclerosis.