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Molecular and Cellular Biochemistry

, Volume 125, Issue 1, pp 19–25 | Cite as

Effects of glycated albumin on mesangial cells: evidence for a role in diabetic nephropathy

  • Fuad N. Ziyadeh
  • Margo P. Cohen
Article

Abstract

Nonenzymatically glycated proteins are preferentially transported across the glomerular filtration barrier, and the glomerular mesangium in diabetes is bathed with serum containing increased concentrations of glycated albumin. We investigated effects of glycated albumin on mesangial cells, which are involved in diabetic nephropathy. [3H]-thymidine incorporation was significantly inhibited when murine mesangial cells were grown in culture media containing human serum that had been nonenzymatically glycated by incubation for 4 days with 28 mM glucose. This inhibition was reversed when monoclonal antibodies that selectively react with Amadori products of glycated albumin were added to the culture media. Purified glycated albumin containing Amadori adducts of the glycation reaction induced significant inhibition of thymidine incorporation and stimulation of Type IV collagen secretion compared with cells cultured in the presence of purified nonglycated albumin. These changes were prevented when monoclonal antibodies specifically reactive with fructosyl-lysine epitopes in glycated albumin were added to the cultures. The antibodies had no effect on growth or collagen production in the presence of nonglycated albumin. The results provide the first evidence directly implicating Amadori adducts in glycated albumin in the pathogenesis of diabetic nephropathy, which is characterized by decreased cellularity in association with expansion of the mesangial matrix.

Key Words

diabetic nephropathy glycated albumin mesangial cells nonenzymatic glycation 

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References

  1. 1.
    Koenig RJ, Blobstein SH, Cerami A: Structure of carbohydrate and hemoglobin A. J Biol Chem 252: 2992–2997, 1972Google Scholar
  2. 2.
    Bunn HF, Gabbay KH, Gallop PM: The glycosylation of hemoglobin: Relevance to diabetes mellitus. Science 200: 21–27, 1978Google Scholar
  3. 3.
    Higgins PJ, Bunn HF: Kinetic analysis of the nonenzymatic glycosylation of hemoglobin. J Biol Chem 256: 5204–5208, 1981Google Scholar
  4. 4.
    Cohen MP: Diabetes and Protein Glycosylation: Measurement and Biologic Relevance, Springer Verlag, New York, 1986Google Scholar
  5. 5.
    Day JF, Ingelbretsen CG, Ingelbretsen WR, Baynes JW, Thorpe SR: Nonenzymatic glucosylation of serum proteins and hemoglobin: Response to changes in blood glucose levels in diabetic rats. Diabetes 29: 524–527, 1980Google Scholar
  6. 6.
    Guthrow CE, Morris MA, Day JF, Thorpe SR, Baynes J: Enhanced nonenzymatic glucosylation of serum albumin in diabetes mellitus. Proc Natl Acad Sci USA 76: 4258–4261, 1979Google Scholar
  7. 7.
    Cohen MP, Hud E: Measurement of plasma glycoalbumin levels with a monoclonal antibody based ELISA. J Immunolog Meth 122: 279–283, 1989Google Scholar
  8. 8.
    Makita Z, Vlassara H, Cerami A, Bucala R: Immunochemical detection of advanced glycosylation end productsin vivo. J Biol Chem 267: 5133–5138, 1992Google Scholar
  9. 9.
    Williams SK, Devenny JJ, Bitensky MW: Micropinocytic ingestion of glycosylated albumin by isolated microvessels: Possible role in the pathogenesis of diabetic microangiopathy. Proc Natl Acad Sci USA 78: 2393–2397, 1981Google Scholar
  10. 10.
    Williams SK, Solenski NJ: Enhanced vesicular ingestion of nonenzymatically glycosylated proteins by capillary endothelium. Microvasc Res 28: 311–321, 1984Google Scholar
  11. 11.
    Williams SK, Siegal RK: Preferential transport of nonenzymatically glycosylated ferritin across the kidney glomerulus. Kid Int 28: 146–152, 1985Google Scholar
  12. 12.
    Agarwal M, Daniels BS: Increased uptake of glycated albumin by glomerular mesangial and epithelial cellsin situ is accompanied by augmented local production of H2O2 Clin Res 40: 179A, 1992Google Scholar
  13. 13.
    McVerry BA, Hopp A, Fisher C, Huehns ER: Production of pseudodiabetic renal glomerular changes in mice after repeated injection of glycosylated proteins. Lancet 2: 738–740, 1980Google Scholar
  14. 14.
    Sabbatini M, Sansone G, Uccello F, Giliberti A, Conte G, Andreucci VE: Early glycosilation products induce glomerular hyperfiltration in normal rats. Kid Int 42: 875–881, 1992Google Scholar
  15. 15.
    Osterby R, Parving H-H, Hommel E, Jorgensen HE, Lokkegard H: Glomerular structure and function in diabetic nephropathy: Early to advanced stages. Diabetes 39: 1057–1063, 1990Google Scholar
  16. 16.
    Saito Y, Kida H, Takeda SI, Yoshimura M, Yokoyama H, Koshino Y, Hattori N: Mesangiolysis in diabetic glomeruli: Its role in the formation of nodular lesions. Kid Int 34: 389–396, 1988Google Scholar
  17. 17.
    Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz F: Structural-functional relationships in diabetic nephropathy. J Clin Invest 74: 1143–1155, 1984Google Scholar
  18. 18.
    Steffes MW, Bilous RW, Sutherland DER, Mauer SM: Cell and matrix components of the glomerular mesangium in Type I diabetes. Diabetes 41: 679–688, 1992Google Scholar
  19. 19.
    Abrass CK, Peterson CV, Raugi GS: Phenotypic expression of collagen types in mesangial matrix of diabetic and nondiabetic rats. Diabetes 37: 1695–1702, 1988Google Scholar
  20. 20.
    Haneda M, Kikkawa R, Horide N, Togawa M, Koya D, Kajiwara N, Ooshima A, Shigeta Y: Glucose enhances Type IV collagen production in cultured rat glomerular mesangial cells. Diabetologia 34: 198–200, 1991Google Scholar
  21. 21.
    Crowley ST, Brownlee M, Edelstein D, Satriano JA, Mori T, Singhal PC, Schlondorff DO: Effects on nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells. Diabetes 40: 540–547, 1991Google Scholar
  22. 22.
    Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker L: Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products. Proc Natl Acad Sci USA 89: 2873–2877, 1992Google Scholar
  23. 23.
    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 Pathol 136: 1339–1348, 1990Google Scholar
  24. 24.
    Ayo SH, Radnik GA, Glass WF, Garoni JA, Rampt E-R, Appling DR, Kreisberg JI: Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high glucose. Am J Physiol 260: F185-F191, 1991Google Scholar
  25. 25.
    Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-β. Kid Int 42: 647–656, 1992Google Scholar
  26. 26.
    Skolnik EY, Yang Z, Makita Z, Radoff S, Kirstein M, Vlassara H: Human and rat mesangial cell receptors for glucose-modified proteins: Potential role in kidney tissue remodelling and diabetic nephropathy. Exp Med 174: 931–939, 1991Google Scholar
  27. 27.
    Esposito C, Geriack H, Brent 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 170:1387–1407, 1989Google Scholar
  28. 28.
    Cohen MP, Hud E: Production and characterization of monoclonal antibodies against human glycoalbumin. J Immunolog Meth 117: 121–129, 1989Google Scholar
  29. 29.
    Kreisberg JI, Karnovsky MJ: Glomerular cells in culture. Kid Int 23: 439–447, 1983Google Scholar
  30. 30.
    Wolf G, Haberstroh U, Neilson EI: Angiotensin II stimulates the proliferation and biosynthesis of Type I collagen in cultured murine mesangial cells. Am J Path 140:95–107, 1992Google Scholar
  31. 31.
    Ney KA, Colley KJ, Pizzo SC: The standardization of the thiobarbituric acid assay for nonenzymatic glucosylation of human serum albumin. Anal Biochem 118: 294–300, 1981Google Scholar
  32. 32.
    Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, Haverty TP: High glucose induces cell hypertrophy and stimulates collagen gene expression in proximal tubule. Am J Physiol 259: F704-F714, 1990Google Scholar
  33. 33.
    Miyata S, Monnier V: Immunohistochemical detection of advanced glycosylation end products in diabetic tissues using monoclonal antibodies to pyralline. J Clin Invest 89: 1102–1112, 1992Google Scholar
  34. 34.
    Sharma K, Ziyadeh FN: The transforming growth factor β system and the kidney. Seminars Nephrol 13: 116–128, 1993Google Scholar
  35. 35.
    Predescu D, Simionescu M, Simionescu N, Palade G: Binding and transcytosis of glycoalbumin by the microvascular endothelium of the murine myocardium: Evidence that glycoalbumin behaves as a bifunctional ligand. J Cell Biol 107: 1729–1738, 1988Google Scholar
  36. 36.
    Wu VY, Cohen MP: Identification of aortic endothelial cell binding proteins for Amadori adducts in glycated albumin. Biochem Biophys Res Comm 193: 1131:1136, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 1993

Authors and Affiliations

  • Fuad N. Ziyadeh
    • 1
    • 2
  • Margo P. Cohen
    • 1
    • 2
  1. 1.Departments of Medicine and BiochemistryUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Penn Center for Molecular Studies of Kidney DiseasesUniversity of PennsylvaniaPhiladelphiaUSA

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