Abstract
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.
Full Text
The Full Text of this article is available as a PDF (556.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Brownlee M., Vlassara H., Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med. 1984 Oct;101(4):527–537. doi: 10.7326/0003-4819-101-4-527. [DOI] [PubMed] [Google Scholar]
- Brownlee M., Vlassara H., Cerami A. Nonenzymatic glycosylation products on collagen covalently trap low-density lipoprotein. Diabetes. 1985 Sep;34(9):938–941. doi: 10.2337/diab.34.9.938. [DOI] [PubMed] [Google Scholar]
- Bucala R., Makita Z., Vega G., Grundy S., Koschinsky T., Cerami A., Vlassara H. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9441–9445. doi: 10.1073/pnas.91.20.9441. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bucala R., Tracey K. J., Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest. 1991 Feb;87(2):432–438. doi: 10.1172/JCI115014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dyer D. G., Blackledge J. A., Thorpe S. R., Baynes J. W. Formation of pentosidine during nonenzymatic browning of proteins by glucose. Identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo. J Biol Chem. 1991 Jun 25;266(18):11654–11660. [PubMed] [Google Scholar]
- Edelstein D., Brownlee M. Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine. Diabetes. 1992 Jan;41(1):26–29. doi: 10.2337/diab.41.1.26. [DOI] [PubMed] [Google Scholar]
- Hayase F., Nagaraj R. H., Miyata S., Njoroge F. G., Monnier V. M. Aging of proteins: immunological detection of a glucose-derived pyrrole formed during maillard reaction in vivo. J Biol Chem. 1989 Mar 5;264(7):3758–3764. [PubMed] [Google Scholar]
- Hogan M., Cerami A., Bucala R. Advanced glycosylation endproducts block the antiproliferative effect of nitric oxide. Role in the vascular and renal complications of diabetes mellitus. J Clin Invest. 1992 Sep;90(3):1110–1115. doi: 10.1172/JCI115928. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kato Y., Tokunaga K., Osawa T. Immunochemical detection of carboxymethylated Apo B-100 in copper-oxidized LDL. Biochem Biophys Res Commun. 1996 Sep 24;226(3):923–927. doi: 10.1006/bbrc.1996.1451. [DOI] [PubMed] [Google Scholar]
- Kennedy L., Baynes J. W. Non-enzymatic glycosylation and the chronic complications of diabetes: an overview. Diabetologia. 1984 Feb;26(2):93–98. doi: 10.1007/BF00281113. [DOI] [PubMed] [Google Scholar]
- Kirstein M., Brett J., Radoff S., Ogawa S., Stern D., Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci U S A. 1990 Nov;87(22):9010–9014. doi: 10.1073/pnas.87.22.9010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knutson V. P. Ligand-independent internalization and recycling of the insulin receptor. Effects of chronic treatment of 3T3-C2 fibroblasts with insulin and dexamethasone. J Biol Chem. 1992 Jan 15;267(2):931–937. [PubMed] [Google Scholar]
- Kume S., Takeya M., Mori T., Araki N., Suzuki H., Horiuchi S., Kodama T., Miyauchi Y., Takahashi K. Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody. Am J Pathol. 1995 Sep;147(3):654–667. [PMC free article] [PubMed] [Google Scholar]
- Lo T. W., Westwood M. E., McLellan A. C., Selwood T., Thornalley P. J. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. J Biol Chem. 1994 Dec 23;269(51):32299–32305. [PubMed] [Google Scholar]
- Makino H., Shikata K., Hironaka K., Kushiro M., Yamasaki Y., Sugimoto H., Ota Z., Araki N., Horiuchi S. Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int. 1995 Aug;48(2):517–526. doi: 10.1038/ki.1995.322. [DOI] [PubMed] [Google Scholar]
- Makita Z., Bucala R., Rayfield E. J., Friedman E. A., Kaufman A. M., Korbet S. M., Barth R. H., Winston J. A., Fuh H., Manogue K. R. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet. 1994 Jun 18;343(8912):1519–1522. doi: 10.1016/s0140-6736(94)92935-1. [DOI] [PubMed] [Google Scholar]
- Makita Z., Radoff S., Rayfield E. J., Yang Z., Skolnik E., Delaney V., Friedman E. A., Cerami A., Vlassara H. Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med. 1991 Sep 19;325(12):836–842. doi: 10.1056/NEJM199109193251202. [DOI] [PubMed] [Google Scholar]
- Makita Z., Vlassara H., Rayfield E., Cartwright K., Friedman E., Rodby R., Cerami A., Bucala R. Hemoglobin-AGE: a circulating marker of advanced glycosylation. Science. 1992 Oct 23;258(5082):651–653. doi: 10.1126/science.1411574. [DOI] [PubMed] [Google Scholar]
- Miyata S., Monnier V. Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibody to pyrraline. J Clin Invest. 1992 Apr;89(4):1102–1112. doi: 10.1172/JCI115690. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miyata T., Inagi R., Iida Y., Sato M., Yamada N., Oda O., Maeda K., Seo H. Involvement of beta 2-microglobulin modified with advanced glycation end products in the pathogenesis of hemodialysis-associated amyloidosis. Induction of human monocyte chemotaxis and macrophage secretion of tumor necrosis factor-alpha and interleukin-1. J Clin Invest. 1994 Feb;93(2):521–528. doi: 10.1172/JCI117002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miyata T., Oda O., Inagi R., Iida Y., Araki N., Yamada N., Horiuchi S., Taniguchi N., Maeda K., Kinoshita T. beta 2-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis. J Clin Invest. 1993 Sep;92(3):1243–1252. doi: 10.1172/JCI116696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Monnier V. M., Kohn R. R., Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci U S A. 1984 Jan;81(2):583–587. doi: 10.1073/pnas.81.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamura Y., Horii Y., Nishino T., Shiiki H., Sakaguchi Y., Kagoshima T., Dohi K., Makita Z., Vlassara H., Bucala R. Immunohistochemical localization of advanced glycosylation end products in coronary atheroma and cardiac tissue in diabetes mellitus. Am J Pathol. 1993 Dec;143(6):1649–1656. [PMC free article] [PubMed] [Google Scholar]
- Niwa T., Katsuzaki T., Momoi T., Miyazaki T., Ogawa H., Saito A., Miyazaki S., Maeda K., Tatemichi N., Takei Y. Modification of beta 2m with advanced glycation end products as observed in dialysis-related amyloidosis by 3-DG accumulating in uremic serum. Kidney Int. 1996 Mar;49(3):861–867. doi: 10.1038/ki.1996.119. [DOI] [PubMed] [Google Scholar]
- Niwa T., Miyazaki S., Katsuzaki T., Tatemichi N., Takei Y., Miyazaki T., Morita T., Hirasawa Y. Immunohistochemical detection of advanced glycation end products in dialysis-related amyloidosis. Kidney Int. 1995 Sep;48(3):771–778. doi: 10.1038/ki.1995.349. [DOI] [PubMed] [Google Scholar]
- Niwa T., Sato M., Katsuzaki T., Tomoo T., Miyazaki T., Tatemichi N., Takei Y., Kondo T. Amyloid beta 2-microglobulin is modified with N epsilon-(carboxymethyl)lysine in dialysis-related amyloidosis. Kidney Int. 1996 Oct;50(4):1303–1309. doi: 10.1038/ki.1996.442. [DOI] [PubMed] [Google Scholar]
- Niwa T., Takeda N., Miyazaki T., Yoshizumi H., Tatematsu A., Maeda K., Ohara M., Tomiyama S., Niimura K. Elevated serum levels of 3-deoxyglucosone, a potent protein-cross-linking intermediate of the Maillard reaction, in uremic patients. Nephron. 1995;69(4):438–443. doi: 10.1159/000188516. [DOI] [PubMed] [Google Scholar]
- Niwa T., Takeda N., Yoshizumi H., Tatematsu A., Ohara M., Tomiyama S., Niimura K. Presence of 3-deoxyglucosone, a potent protein crosslinking intermediate of Maillard reaction, in diabetic serum. Biochem Biophys Res Commun. 1993 Oct 29;196(2):837–843. doi: 10.1006/bbrc.1993.2325. [DOI] [PubMed] [Google Scholar]
- Njoroge F. G., Sayre L. M., Monnier V. M. Detection of D-glucose-derived pyrrole compounds during Maillard reaction under physiological conditions. Carbohydr Res. 1987 Sep 15;167:211–220. doi: 10.1016/0008-6215(87)80280-x. [DOI] [PubMed] [Google Scholar]
- Reddy S., Bichler J., Wells-Knecht K. J., Thorpe S. R., Baynes J. W. N epsilon-(carboxymethyl)lysine is a dominant advanced glycation end product (AGE) antigen in tissue proteins. Biochemistry. 1995 Aug 29;34(34):10872–10878. doi: 10.1021/bi00034a021. [DOI] [PubMed] [Google Scholar]
- Schmidt A. M., Hori O., Chen J. X., Li J. F., Crandall J., Zhang J., Cao R., Yan S. D., Brett J., Stern D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995 Sep;96(3):1395–1403. doi: 10.1172/JCI118175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sell D. R., Monnier V. M. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J Biol Chem. 1989 Dec 25;264(36):21597–21602. [PubMed] [Google Scholar]
- Smith M. A., Taneda S., Richey P. L., Miyata S., Yan S. D., Stern D., Sayre L. M., Monnier V. M., Perry G. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5710–5714. doi: 10.1073/pnas.91.12.5710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Soulis-Liparota T., Cooper M., Papazoglou D., Clarke B., Jerums G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991 Oct;40(10):1328–1334. doi: 10.2337/diab.40.10.1328. [DOI] [PubMed] [Google Scholar]
- Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
- Szwergold B. S., Kappler F., Brown T. R. Identification of fructose 3-phosphate in the lens of diabetic rats. Science. 1990 Jan 26;247(4941):451–454. doi: 10.1126/science.2300805. [DOI] [PubMed] [Google Scholar]
- Vitek M. P., Bhattacharya K., Glendening J. M., Stopa E., Vlassara H., Bucala R., Manogue K., Cerami A. Advanced glycation end products contribute to amyloidosis in Alzheimer disease. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4766–4770. doi: 10.1073/pnas.91.11.4766. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vlassara H., Fuh H., Donnelly T., Cybulsky M. Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med. 1995 May;1(4):447–456. [PMC free article] [PubMed] [Google Scholar]
- Vlassara H., Striker L. J., Teichberg S., Fuh H., Li Y. M., Steffes M. Advanced glycation end products induce glomerular sclerosis and albuminuria in normal rats. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11704–11708. doi: 10.1073/pnas.91.24.11704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yan S. D., Chen X., Schmidt A. M., Brett J., Godman G., Zou Y. S., Scott C. W., Caputo C., Frappier T., Smith M. A. Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7787–7791. doi: 10.1073/pnas.91.16.7787. [DOI] [PMC free article] [PubMed] [Google Scholar]