Laboratory Investigation

Kidney International (1997) 51, 27–35; doi:10.1038/ki.1997.4

Nonenzymatically glycated albumin (Amadori adducts) enhances nitric oxide synthase activity and gene expression in endothelial cells

Alessandro Amore1, Paola Cirina1, Stefania Mitola1, Licia Peruzzi1, Bruno Gianoglio1, Ivana Rabbone1, Carla Sacchetti1, Franco Cerutti1, Caterina Grillo1 and Rosanna Coppo1

1Nephrology and Dialysis Department, Central Laboratory, Regina Marghenta Children's Hospital, and Pediatric Clinic, University of Torino, Torino, Italy

Correspondence: Alessandro Amore MD, Divisione Nefrologia e Dialisi, Ospedale Regina Margherita, Piazza Polonia, 94, 10126 Torino, Italy.

Received 7 February 1996; Revised 5 August 1996; Accepted 5 August 1996.

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Abstract

Nonenzymatically glycated albumin (Amadori adducts) enhances nitric oxide synthase activity and gene expression in endothelial cells. Hyperglycemia is considered to induce diabetic nephropathy through nonenzymatic glycation of proteins. Since hyperfiltration is likely to be the mechanism initiating the glomerular lesions, we investigated the effects of Amadori glucose adducts in serum albumin on the production of vasoactive mediators, including nitric oxide (NO) and eicosanoids, by endothelial cells (EC). Amadori adducts of glycated albumin induced a dose-response increase in NO synthase activity of murine endothelioma cells, up to 16.4 plusminus 2.1-fold increase of basal values (P < 0.0001) at concentrations of 35 mg/ml mimiking physiological serum albumin concentration, and 4.6 plusminus 0.8-fold increase at 17 mg/ml (P < 0.001). The effect was still detectable with glycated albumin 1.7 mg/ml, which approaches its estimated concentration in diabetic serum (1.6 plusminus 0.3-fold increase, P < 0.05) The phenomenon was reproducible in human umbilical vein endothelial cells, though to a lesser extent, and further studies on murine EC were employed. The mRNA encoding for inducible NO synthase was overexpressed in EC incubated with Amadori adducts of glycated albumin in comparison to native albumin. Glycated albumin induced increased mRNA expression and synthesis of TNF-alpha. The stimulatory effect induced by glycated albumin on NO synthase activity was almost completely inhibited by anti TNF alpha antibodies. 3H-thymidine incorporation by EC was significantly inhibited when cells were grown in presence of glycated albumin (P < 0.001), and the phenomenon was abolished by the coincubation of the NO competitive inhibitor L-NAME. The early glycosylation products increased thromboxane production (P < 0.001), while prostaglandin E2 synthesis was unaffected. These data indicate that Amadori products of glycated albumin modulate NO synthase activity and eicosanoid balance in EC. These effects may be relevant to the hemodynamic changes in the early phases of diabetic nephropathy and in the lasting progression to sclerosis.

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References

  1. Us Renal Data System: USRDS 1992 Annual Data Report. Bethesda, National Institutes of Health, National Institute of Diabetes and Digestive Kidney Diseases, 1992
  2. Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-beta. Kidney Int 42:647–656, 1992 | PubMed | ISI | ChemPort |
  3. Lorenzi M, Cagliero E, Toledo S: Glucose toxicity for human endothelial cells in culture: Delayed replication, disturbed cell cycle, and accellerated death. Diabetes 34:621–627, 1985 | PubMed | ISI | ChemPort |
  4. Haneda M, Kikkawa R, Horide N, Togawa M, Koya D, Kasiwara N, Ooshima A, Shigeta Y: Glucose enhanced type IV collagen production in cultured mesangial cells. Diabetologia 34:198–200, 1991 | Article | PubMed | ISI | ChemPort |
  5. Ayo SH, Radnik GA, Garoni JA, Glass WF, Kreisberg JI: High glucose causes an increase in extracellular matrix proteins in cultured mesangial cells. Am J Physiol 260:F185–F191, 1991 | PubMed | ISI | ChemPort |
  6. Kikkawa R, Uremura K, Haneda M, Arimura T, Ebata K, Shigeta Y: Evidence for the existence of polyol pathway in cultured rat mesangial cells. Diabetes 36:240–243, 1987 | PubMed | ISI | ChemPort |
  7. Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border W: Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 90:1814–1818, 1993 | Article | PubMed | ChemPort |
  8. Makita Z, Radoff S, Rayfield EJ, Yang Z, Skolnik E, Delaney V, Friedman EA, Cerami A, Vlassara H: Advanced glycosylation end products in patients with diabetic nephropathy. N Engl J Med 325:836–842, 1991 | PubMed | ISI | ChemPort |
  9. Predescu D, Simionescu M, Simionescu N, Palade G: Binding and transcytosis by the microvascular endothelium of the murine myocardium: Evidence that glycoalbumin behaves as a bifunctional ligand. J Cell Biol 107:1729–1738, 1988
  10. Cohen MP, Ziyadeh FN: Amadori glucose adducts modulate mesangial cell growth and collagen gene expression. Kidney Int 45:475–484, 1995
  11. Cohen MP: Diabetes and Protein Glycosylation: Measurement and Biologic Relevance. New York, Springer Verlag, 1986
  12. Brownlee M, Cerami A, Vlassara H: Adavenced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321, 1988 | PubMed | ISI | ChemPort |
  13. Guthrow CE, Morris MA, Day JF, Thorpe SR, Baynes J: Enhanced non enzymatic glucosylation of serum albumin in diabetes mellitus. Proc Natl Acad Sci USA 76:4258–4261, 1979 | PubMed | ChemPort |
  14. Brownlee M, Vlassara H, Cerami A: Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med 101:527–537, 1984 | PubMed | ISI | ChemPort |
  15. Njoroge FG, Monnier VM: The chemistry of the Maillard reaction under physiological conditions: A review. Prog Clin Biol Res 304:85–107, 1989 | ChemPort |
  16. Ledl F, Beck J, Sengl M, Osiander H, Estendorfer S, Severin T, Huber B: Chemical pathways of the Maillard reaction. Prog Clin Biol Res 304:23–42, 1989
  17. Monnier VM, Wishwanath V, Frank KE, Elmets CA, Dauchot P, Kohn RR: Relation between complications of Type I diabetes mellitus and collagen-linked fluorescence. N Engl J Med 314:403–408, 1986
  18. Monnier VM, Kohon RR, Cerami A: Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci USA 81:583–587, 1984 | Article | PubMed | ChemPort |
  19. Schnider SL, Kohn RR: Glucosylation of human collagen in aging and diabetes mellitus. J Clin Invest 66:1179–1181, 1980 | PubMed | ISI | ChemPort |
  20. Day JF, Ingelbretsen WR, Baynes JW, Thorpe SR: Nonenzymatic glycosylation of serum proteins and hemoglobin: Response to changes in blood glucose levels in diabetic rats. Diabetes 29:524–527, 1980 | PubMed | ISI | ChemPort |
  21. Cohen MP, Hud E, Wu VY: Amelioration of diabetic nephropathy by treatment with monoclonal antibodies against glycated albumin. Kidney Int 45:1673–1679, 1994 | PubMed | ISI | ChemPort |
  22. Cohen MP, Hud E: Production and characterization of monoclonal antibodies against human glycoalbumin. J Immunol Meth 117:121–129, 1989
  23. Brochner-Mortensen J: Glomerular filtration rate and extracellular fluid volumes during normoglycemia and moderate hyperglycemia in diabetes. Scand J Clin Lab Invest 32:311–316, 1973
  24. Hostetter TH, Troy JL, Brenner BM: Glomerular hemodinamics in experimental diabetes. Kidney int 19:410–415, 1981 | PubMed | ISI | ChemPort |
  25. Hostetter TH, Rennke HG, Brenner BM: The case of intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72:375–380, 1982 | Article | PubMed | ISI | ChemPort |
  26. Sabbatini M, Sansone G, Uccello F, Giliberti A, Conte G, Andreucci VE: Early glycosylation products induce glomerular hyperfiltration in normal rats. Kidney Int 42:875–881, 1992 | PubMed | ISI | ChemPort |
  27. Moncada S, Palmer RMJ, Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142, 1991 | PubMed | ISI | ChemPort |
  28. Bank N, Aynedjian HS: Role of EDRF (nitric oxide) in diabetic renal hyperfiltration. Kidney Int 43:1306–1312, 1993 | PubMed | ISI | ChemPort |
  29. Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilation in experimental diabetes. J Clin Invest 87:432–438, 1991 | PubMed | ISI | ChemPort |
  30. Hasegawa G, Nakano K, Sawada M, Uno K, Shibayama Y, Ienaga K, Kondo M: Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy. Kidney Int 40:1007–1012, 1991 | PubMed | ISI | ChemPort |
  31. Beutler B, Cerami A: Cachectin: More than tumor necrosis factor. N Engl J Med 316:379–385, 1987 | PubMed | ChemPort |
  32. Bussolino F, De Rossi M, Sica A, Colotta F, Wang JM, Bocchietto E, Padura IM, Bosia A, Dejand E, Mantovani A: Murine endothelioma cell lines transformed by polyoma middle T oncogene as target for and producers of cytokines. J Immunol 147:2122–2129, 1993
  33. Williams RL, Courtneidge SA, Wagner EF: Embryonic lethalities and endothelial tumors in chimeric mice expressing polyoma virus middle T oncogene. Cell 52:121–131, 1988 | Article | PubMed | ISI | ChemPort |
  34. Garlanda C, Parravicini C, Sirono M, De Rossi M, Wainstok DE, Calamanovici R, Carozzi F, Bussolino F, Colotta F, Mantovani A, Vecchi A: Progressive growth in immunodeficient mice and host cell recruitment by mouse endothelial cells transformed by polyoma middle T: Implications for the pathogenesis of opportunistic tumors. Proc Natl Acad Sci USA 91:7291–7295, 1994 | Article | PubMed | ChemPort |
  35. Jaffe EA, Nachman RL, Becker CG, Minik CR: Culture of human endothelial cells derived from umbilical vein. J Clin Invest 52:2745–2756, 1973 | PubMed | ISI | ChemPort |
  36. Brownlee M, Vlassara A, Kooney A, Ulrich P, Cerami A: Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking. Science 232:1629–1632, 1986 | Article | PubMed | ISI | ChemPort |
  37. Xie QW, Cho HJ, Calaycay, Mumford RA, Swiderek TD, Lee TD, Ding A, Troso T, Nathan CJ: Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256:225–228, 1992 | Article | PubMed | ISI | ChemPort |
  38. Gross SS: Nitric oxide: Pathophysiological mechanisms. Annu Revu Physiol 57:737–769, 1995
  39. Cohen MP, Hud E: Measurement of plasma glycoalbumin levels with a monoclonal antibody based ELISA. J Immunol Meth 122:279–283, 1989 | Article | ISI | ChemPort |
  40. Stuehr DJ, Griffith OW: Mammalian nitric oxide synthases. Adv Enzymol 65:287–346, 1992 | PubMed | ISI | ChemPort |
  41. Stamler JS, Singel DJ, Loscalzo J: Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902, 1992 | Article | PubMed | ISI | ChemPort |
  42. Pou S, Pou WS, Bredt DS, Snyder SH, Rosen GM: Generation of superoxide by purified brain nitric oxide synthase. J Biol Chem 267:24173–24176, 1992 | PubMed | ISI | ChemPort |
  43. Raij L, Baylis C: Glomerular actions of nitric oxide. Kidney Int 48:20–32, 1995 | PubMed | ISI | ChemPort |
  44. Tesfamarian B, Brown ML, Deykin D, Cohen RA: Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 85:929–932, 1990
  45. Weidmann P, Beretta-Piccolo C, Trost BN: Pressor factors and responsiveness in hypertension accompanayng diabetes mellitus. Hypertension 7-II:33–42, 1985
  46. Derubertis FR, Craven PA: Activation of protein Kinase C in glomerular cells in diabetes. Mechanisms of potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 43:1–8, 1993
  47. De Rubertis FR, Craven PA: Eicosanoids in the pathogenesis of the functional and structural alterations of the kideny in diabetes. Am J Kidney Dis 22:727–735, 1993 | PubMed | ChemPort |
  48. Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FC: Structural-functional relationship in diabetic nephropathy. J Clin Invest 74:1143–1155, 1984 | PubMed | ISI | ChemPort |
  49. Cohen MP, Hud E, Wu VY, Ziyadeh FN: Glycated albumin modified by Amadori adducts modulates aortic endothelial cell biology. Mol Cell Biochem 143:73–79, 1995 | Article | PubMed | ISI | ChemPort |
  50. Cohen MP, Sharma K, Jin Y, Wu VY, Tomaszewski J, Ziyadeh FN: Prevention of Diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest 95:2338–2345, 1995 | PubMed | ISI | ChemPort |
  51. Pfeilschifter J, Pignat W, Vosbek K, Marki F: Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and pkhospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun 159:385–394, 1989 | Article | PubMed | ISI | ChemPort |

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