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DOI: 10.1055/s-2002-33478
Aminoguanidine Pyridoxal Adduct is Superior to Aminoguanidine for Preventing Diabetic Nephropathy in Mice
Publication History
Received: 22 November 2001
Accepted after revision: 27 March 2002
Publication Date:
21 August 2002 (online)
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Abstract
Aminoguanidine inhibits the formation of advanced glycation end-products, and has been extensively examined in animals. However, administration of aminoguanidine decreases the hepatic content of pyridoxal phosphate. In order to avoid this problem, we developed an aminoguanidine pyridoxal Schiff base adduct and examined its efficacy in vitro as well as in a model of diabetic nephropathy. Mice with streptozotocin-induced diabetes were treated with aminoguanidine or aminoguanidine pyridoxal adduct for 9 weeks. An in vitro study was also performed to assess the antioxidant activity of aminoguanidine and its pyridoxal adduct. Neither drug altered glycemic control. Aminoguanidine pyridoxal adduct significantly improved urinary albumin excretion by 78.1 % compared with the diabetic control, and also had a better preventive effect on the progression of renal pathology than aminoguanidine did. Inhibition of glycation by both drugs was similar, but the antioxidant activity of the pyridoxal adduct was far superior. These findings suggest that aminoguanidine pyridoxal adduct may be superior to aminoguanidine, as it not only prevents vitamin B6 deficiency but is also better at controlling diabetic nephropathy, as this adduct inhibits oxidation as well as glycation.
Key words
Aminoguanidine - Pyridoxal - Vitamin B6 - Glycation - Antioxidant - Nephropathy
References
- 1 Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science. 1986; 232 1629-1632
- 2 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 USA. 1994; 27 9441-9445
- 3 Soulis L T, Cooper M, Papazoglou D, Clarke B, Jerums G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozotocin-induced diabetic rats. Diabetes. 1991; 40 1328-1334
- 4 Havivi E, Bar O n, Reshef A, Stein P, Raz I. Vitamins and trace metals status in non-insulin dependent diabetes mellitus. Int J Vitam Nutr Res. 1991; 61 328-333
- 5 Khatami M, Suldan Z, David I, Li W, Rockey J H. Inhibitory effects of pyridoxal phosphate, ascorbate and aminoguanidine on nonenzymatic glycosylation. Life Sci. 1988; 43 1725-1731
- 6 Khatami M. Role of pyridoxal phosphate/pyridoxine in diabetes. Inhibition of nonenzymatic glycosylation. Ann NY Acad Sci. 1990; 585 502-504
- 7 Folkers K, Ellis J M, Watanabe T, Saji S, Kaji M. Biochemical evidence for a deficiency of vitamin B6 in the carpal tunnel syndrome based on a crossover clinical study. Proc Natl Acad Sci USA. 1978; 75 3410-3412
- 8 Ellis J M, Folkers K, Minadeo M, VanBuskirk R, Li-Jun X, Tamagawa H. A deficiency of vitamin B6 is a plausible molecular basis of the retinopathy of patients with diabetes mellitus. Biochem Biophys Res Commun. 1991; 179 615-619
- 9 Stampfer M J, Melinow M R, Willett W C, Newcomer L M, Upson B, Ullmann D, Tishler P V, Hennekens C H. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. J Am Med Assoc. 1992; 268 877-881
- 10 Okada M, Ayabe Y. Effects of aminoguanidine and pyridoxal phosphate on glycation reaction of aspartate aminotransferase and serum albumin. J Nutr Sci Vitaminol. 1995; 41 43-50
- 11 Taguchi T, Sugiura M, Hamada Y, Miwa I. In vivo formation of Schiff base of aminoguanidine with pyridoxal phosphate. Biochem Pharmacol. 1998; 55 1667-1671
- 12 Taguchi T, Sugiura M, Hamada Y, Miwa I. Inhibition of advanced protein glycation by a Schiff base between aminoguanidine and pyridoxal. Eur J Pharmacol. 1999; 378 283-289
- 13 Giardino I, Fard K A, Hatchell L D, Brownlee M. Aminoguanidine inhibits reactive oxygen species formation, lipid peroxidation, and oxidant-induced apoptosis. Diabetes. 1998; 47 1114-1120
- 14 Takeuchi M, Makita Z, Yanagisawa K, Kameda Y, Koike T. Detection of noncarboxymethyllysine and carboxymethyllysine advanced glycation end products (AGE) in serum of diabetic patients. Mol Med. 1999; 5 393-405
- 15 Makita Z, Vlassara H, Cerami A, Bucala R. Immunochemical detection of advanced glycosylation end products in vivo. J Biol Chem. 1992; 15 5133-5138
- 16 Endo M, Yanagisawa K, Tsuchida K, Okamoto T, Matsushita T, Higuchi M, Matsuda A, Takeuchi M, Makita Z, Koike T. Increased levels of vascular endothelial growth factor and advanced glycation end products in aqueous humor of patients with diabetic retinopathy. Horm Metab Res. 2001; 33 317-22
- 17 Lane P H, Steffes M W, Mauer S M. Estimation of glomerular volume: A comparison of four methods. Kidney Int. 1992; 41 1085-1089
- 18 Jensen E B, Gundersen H JG, Osterby R. Determination of membrane thickness distribution from orthogonal intercepts. J Microsc. 1979; 115 19-33
- 19 Guesdon J L, Ternynik T, Avrameas S. The use of avidin-biotin interaction in immunoenzyme techniques. J Histochem Cytochem. 1979; 27 1131-1139
- 20 Russell J, Ness J, Chopra M, McMurray J, Smith E W. The assessment of the OH-scavenging action of therapeutic agents. J Pharm Biomed Anal. 1994; 12 863-866
- 21 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; 19 836-842
- 22 Makita Z, Bucala R, Rayfield E J, Friedman E A, Kaufman A M, Korbet S M, Barth R H, Winston J A, Fuh H, Monogue K R, Cerami A, Vlassara H. Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure. Lancet. 1994; 18 1519-1522
- 23 Rocic B, Turk Z, Misur I, Vucic M. Effect of creatine on glycation of albumin in vitro. Horm Metab Res. 1995; 27 511-512
- 24 Tsuchida K, Makita Z, Yamagishi S, Atsuni T, Miyoshi H, Obara S, Ishida M, Ishikawa S, Yasumura K, Koike T. Suppression of transforming growth factor-beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195. Diabetologia. 1999; 42 579-588
- 25 Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, Wagla D, Shin D, Terlecky I, Bucala R, Cerami A, Egan J, Ulrich P. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature. 1996; 18 275-278
- 26 He C, Sabol J, Mitsuhashi T, Vlassara H. Dietary glycotoxins: Inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration. Diabetes. 1999; 48 1308-1315
- 27 Gilbert R E, Cooper M E. The tubulointerstitum in progressive diabetic kidney disease: More than an aftermath of glomerular injury?. Kidney Int. 1999; 56 1627-1637
- 28 D’Agord S B, Lacchini S, Bertoluci C M, Irigoyen C M, Machado F U, Schmid H. Increased renal GLUT1 abundance and urinary TGF-B1 in Streptozotocin-induced diabetic rats: Implications for the development of nephropathy complicating diabetes. Horm Metab Res. 2001; 33 664-669
- 29 Nyengaard J R, Chang K, Berhorst S, Reiser K M, Williamson J R, Tilton R G. Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats. Diabetes. 1997; 46 94-106
- 30 Soulis T, Cooper M E, Vranes D, Bucala R, Jerums G. Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kid Int. 1996; 50 627-634
- 31 Onorato J M, Jenkins A J, Thorpe S R, Baynes J W. Pyridoxamine, an inhibitor of advanced glycation reactions, also inhibits advanced lipoxidation reactions. J Biol Chem. 2000; 275 21 177-21 184
- 32 Booth A A, Khalifah R G, Todd P, Hudson B G. In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). J Biol Chem. 1997; 272 5430-5437
- 33 Khalifah R G, Baynes J W, Hudson B G. Amadorins: Novel post-Amadori inhibitors of advanced glycation reactions. Biochem Biophys Res Commun. 1999; 257 251-258
K. Yanagisawa, M.D., Ph.D.
Department of Internal Medicine II, Hokkaido University School of Medicine
Sapporo, 060-8638 · Japan
Phone: + 81 (11) 716 11 61 (Ex. 59 17)
Fax: + 81 (11) 706 77 10 ·
Email: kyanagi@med.hokudai.ac.jp