J Korean Med Sci.  2009 Jan;24(Suppl 1):S189-S194. 10.3346/jkms.2009.24.S1.S189.

The Breakdown of Preformed Peritoneal Advanced Glycation End Products by Intraperitoneal Alagebrium

• Lee YK
• Lee JY
• Kim JS
• Won KB
• Kang HJ
• Jang TJ
• Tak WT
• Lee JH

• KMID: 1778161
• DOI: http://doi.org/10.3346/jkms.2009.24.S1.S189

Abstract

It has been demonstrated that inhibitors of advanced glycation end products (AGE), such as aminoguanidine, can suppress peritoneal AGE in rats on peritoneal dialysis (PD). However, it is unknown whether late administration of a putative crosslink breaker, alagebrium, could reverse peritoneal AGE. We therefore compared alagebrium with aminoguanidine in their ability to reverse peritoneal AGE in rats on PD. Male Sprague-Dawley rats were randomly divided into 3 groups: group I dialyzed with 4.25% glucose solution for all exchanges; group II dialyzed with 4.25% glucose solution containing aminoguanidine, and group III dialyzed with 4.25% glucose solution containing alagebrium for last 8 weeks of 12-week dialysis period. Dialysis exchanges were performed 2 times a day for 12 weeks. Immunohistochemistry was performed using a monoclonal anti-AGE antibody. One-hour PET was performed for comparison of transport characteristics. The immunolabelling of AGE in peritoneal membrane was markedly decreased in the alagebrium group. Consistent with this, the alagebrium group exhibited significantly higher D/Do glucose and lower D/P urea, suggesting low peritoneal membrane transport. But there were no significant differences between the control and the aminoguanidine group. These results suggest that the alagebrium may be the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in rats on PD.

Keyword

Advanced Glycation End Products; Aminoguanidine; Alagebrium; Peritoneal Dialysis

MeSH Terms

Animals
Biological Transport
Body Weight
Cell Membrane/metabolism
Glycosylation End Products, Advanced/*metabolism
Guanidines/metabolism
Immunohistochemistry/methods
Male
Peritoneal Dialysis/*methods
Peritoneum/metabolism/*pathology
*Permeability
Rats
Rats, Sprague-Dawley

Figure

• 

  Fig. 1 Immunostaining for advanced glycation end products in the peritoneal mesothelial cell. The mesothelial cells of group I (A) and group II (B) show moderate to strong expression. However, the mesothelial cells of group III (C) show weak expression.

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  Fig. 2 Immunostaining for advanced glycation end products in the peritoneal vascular wall. The vessels of group I (A) and group II (B) show moderate to strong expression. However, the vessels of group III (C) show weak expression.

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  Fig. 3 Semiquantitative scoring of advanced glycation end products immunohistology. *p<0.05 (control vs. alagebrium); †p<0.05 (aminoguanidine vs. alagebrium).

Reference

1. Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, clinical implications for diabetes and aging. Lab Invest. 1994. 70:138–151.

2. Vlassara H. Recent progress on the biologic and clonical significance of advanced glycosylation end-products. J Lab Clin Med. 1994. 124:19–39.

3. Makita Z, Bucala R, Rayfield EJ, Friedman EA, Kaufman AM, Korbet SM, Barth RH, Winston JA, Fuh H, Manogue KR, Cerami A, Vlassara H. Reactive glycosylation end products in diabetic uraemia and treatment of renal failure. Lancet. 1994. 343:1519–1522.

4. Vlassara H. Serum advanced glycosylation end-products: a new class of uremic toxins? Blood Purif. 1994. 12:54–59.

5. Kennedy L, Baynee JW. Non-enzymatic glycosylation and the chronic compliacations of diabetes. An overview Diabetologia. 1984. 26:93–98.

6. Brownlee M, Cerami A, VLassara H. Advanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular diseases. Diabetes Metab Rev. 1988. 4:437–451.

7. Lee EA, Oh JH, Lee HA, Kim SI, Park EW, Park KB, Park MS. Structual and fuctional alterations of the poritoneaum after prolonged exposure to dialysis solutions: role of aminoguanidine. Perit Dial Int. 2001. 21:245–253.

8. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A. Amionguanidine prevents diabetes-induced arterial wall protein cross-linking. Science. 1986. 232:1629–1632.

9. Vlassara H, Fuh H, Makita Z, Krungkrai S, Cerami A, Bucala R. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetic and aging complications. Pro Natl Acad Sci USA. 1992. 89:12043–12047.

10. Cooper ME, Thallas V, Forbes J, Scalbert E, Sastra S, Darby I, Soulis T. The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation. Diabetologia. 2000. 43:660–664.

11. Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J, Wagle D, Shih D, Terlecky I, Bucala R, Cerami A, Egan H, Ulrich P. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature. 1996. 382:275–278.

12. Wolffenbuttel BH, Boulanger CM, Crijns FR, Huijberts MS, Poitevin P, Swennen GN, Vasan S, Egan JJ, Ulrich P, Cerami A, Levy BI. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc Natl Acad Sci USA. 1998. 95:4630–4634.

13. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, DeGroof RC, Lakatta EG. Improved arterial compliance by a novel advanced glycation endproduct crosslink breaker. Circulation. 2001. 104:1464–1470.

14. Forbes JM, Thallas V, Thomas MC, Founds HW, Burns WC, Jerums G, Cooper ME. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 2003. 17:1762–1764.

15. Forbes JM, Yee LT, Thallas V, Markus Lassila M, Candido R, Jandeleit-Dahm KA, Thomas MC, Burns WC, Deemer EK, Thorpe SR, Cooper MF, Allen TJ. Advanced glycation end product interventions reduce diabetes-accelerated atherosclerosis. Diabetes. 2004. 53:1813–1823.

16. Forbes JM, Cooper ME, Thallas V, Burns WC, Thomas MC, Brammar GC, Lee F, Grant SL, Burrell LA, Jerums G, Osicka TM. Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy. Diabetes. 2002. 51:3274–3282.

17. Tak WT, Kim SK, Lee JY, Kang HJ, Kim ES, Lee JH. The suppression of peritoneal advanced glycosylation end product formation by intraperitoneal aminoguanidine. Korean J Nephrol. 2006. 25:23–33.

18. Struijk DG, Krediet RT, Kookmen GC, Hoek FJ, Boechoten EW, Reijden HJ, Arisz L. Functional characteristics of the peritoneal membrane in long-term continous ambulatory peritoneal dialysis. Nephron. 1991. 59:213–220.

19. Tooke JE. Microcirculation and diabetes. Br Med Bull. 1989. 45:206–223.

20. Rippe B. Pathophysiological description of the ultrafiltration changes of the peritoneal membrane during long-term continuous ambulatory peritoneal dialysis. Blood Purif. 1994. 12:211–220.

21. Tsilibary EC, Charonis AS, Reger LA, Dege JE, Furcht LT. The effect of nonenzymatic glycosylation on the binding of the main noncollagenous NC1 domain to the type IV collagen. J Biol Chem. 1998. 263:4302–4308.

22. Chraronis AS, Reger LA, Dege JE, Kouzi-Koliakos K, Furcht LT, Wohlhueter RM, Tsilibary EC. Laminin alterations after in vitro nonenzymatic glycosylation. Diabetes. 1990. 39:807–814.

23. Esposito C, Gerlach H, Brett J, Stern D, Vlassara H. Endothelial receptor-mediated binding of glucose modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant properties. J Exp Med. 1989. 170(4):1387–1407.