The Steno Hypothesis and Glomerular Basement Membrane Biochemistry in Diabetic Nephropathy

  • Allan Kofoed-Enevoldsen


So far, at the biochemical level, the pathogenesis of diabetic nephropathy is unresolved. Not surprisingly perhaps since even a our understanding of the biochemical fundaments of normal glomerular function remains incomplete. In addition, when exploring the pathogenesis of diabetic nephropathy, we are likely to witness the composite course of succeeding stages, each of which may have its own pathogenetic trait.


Diabetic Nephropathy Glomerular Basement Membrane Urinary Albumin Excretion IDDM Patient Poor Metabolic Control 
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  1. 1.
    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. Diabetologia 1989; 32: 219–26.PubMedCrossRefGoogle Scholar
  2. 2.
    Mathiesen ER. Prevention of diabetic nephropathy: Microalbuminuria and perspectives for intervention in insulin-dependent diabetes. Dan Med Bull 1993; 40: 273–285.PubMedGoogle Scholar
  3. 3.
    Kanwar YS. Biophysiology of glomerular filtration and proteinuria. Lab Invest 1984; 51: 7–21.PubMedGoogle Scholar
  4. 4.
    Deen WM, Satvat B. Determinants of the glomerular filtration of proteins. Am J Physiol 1981; 241: F162–F170.PubMedGoogle Scholar
  5. 5.
    Viberti GC, Mackintosh D, Keen H. Determinants of the penetration of proteins through the glomerular barrier in IDDM. Diabetes 1983; 32: Suppl. 2: 92–95.PubMedCrossRefGoogle Scholar
  6. 6.
    Deckert T, Kofoed-Enevoldsen A, Vidal P, Nørgaard K, Andreasen HB, Feldt-Rasmussen B. Size-and charge selectivity of glomerular filtration in IDDM patients with and without albuminuria. Diabetologia 1993; 36: 244–251.PubMedCrossRefGoogle Scholar
  7. 7.
    Bangstad H-J, Kofoed-Enevoldsen A, Dahl-Jørgensen K, Hanssen KF. Glomerular charge selectivity and the influence of improved blood glucose control. Diabetologia 1992; 35: 1165–1169.PubMedCrossRefGoogle Scholar
  8. 8.
    Myers BD, Winetz JA, Chui F, Michaels AS. Mechanisms of proteinuria in diabetic nephropathy — A study of glomerular barrier function. Kidney Int 1982; 21: 633–641.PubMedCrossRefGoogle Scholar
  9. 9.
    Deen WM, Bridges CR, Brenner BM, Myers BD. Heterosporous model of glomerular size selectivity, application to normal and nephrotic humans. Am J Physiol 1985; 249: F374–F389.PubMedGoogle Scholar
  10. 10.
    Kofoed-Enevoldsen A. Heparan sulphate in the metabolism of diabetic nephropathy. Diabetes/Metabolism Reviews 1995; 11: 137–160.PubMedCrossRefGoogle Scholar
  11. 11.
    Vernier RL, Steffes MW, Sisson-Ross S, Mauer SM. Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Kidney Int 1992; 41: 1070–1080.PubMedCrossRefGoogle Scholar
  12. 12.
    Rosenzweig LJ, Kanwar Y. Removal of sulfated (heparan sulfate) or nonsulfated (hyaluronic acid) glycosaminoglycans results in increased permeability of the glomerular basement membrane to 125I-bovine serum albumin. Lab Invest 1982; 47: 177–184.PubMedGoogle Scholar
  13. 13.
    Van Den Born J, Van Den Heuvel LPWJ, Bakker MAH, Veerkamp JH, Assmann KJM, Berden JHM. A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats. Kidney Int 1992; 41: 115–123.PubMedCrossRefGoogle Scholar
  14. 14.
    Tarsio JF, Reger LA, Furcht LT. Molecular mechanisms in basement membrane complications of diabetes. Diabetes 1988; 37: 532–539.PubMedCrossRefGoogle Scholar
  15. 15.
    Wahl P, Deppermann D, Hasslacher C. Biochemistry of glomerular basement membrane of the normal and diabetic human. Kidney Int 1982; 21: 744–749.PubMedCrossRefGoogle Scholar
  16. 16.
    Shimomura H, Spiro RG. Studies on macromolecular components of human glomerular basement membrane and alterations in diabetes. Diabetes 1987; 36: 374–381.PubMedCrossRefGoogle Scholar
  17. 17.
    Parthasarathy N, Spiro RG. Effect of diabetes on the glycosaminoglycan component of the human glomerular basement membrane. Diabetes 1982; 31: 738–741.PubMedCrossRefGoogle Scholar
  18. 18.
    Nerlich A, Schleicher E. Immunohistochemical localization of extracellular matrix components in human diabetic glomerular lesions. Am J Pathol 1991; 139: 889–899.PubMedGoogle Scholar
  19. 19.
    Van Den Born J, Van Den Heuvel LPWJ, Bakker MAH, Veerkamp JH, Assmann KJM, Weening JJ, Berden JHM. The distribution of GBM heparan sulfate proteoglycan core protein and side chains in human glomerular diseases by monoclonal antibodies. Kidney Int 1993; 43: 454–463.PubMedCrossRefGoogle Scholar
  20. 20.
    Reddi AS, Ramamurthi R, Miller M, Dhuper S, Lasker N. Enalapril improves albuminuria by preventing glomerular loss of heparan sulfate in diabetic rats. Biochem Med Metab Biol 1991; 45: 119–131.PubMedCrossRefGoogle Scholar
  21. 21.
    Klein DJ, Brown DM, Oegema TR. Glomerular proteoglycans in diabetes. Diabetes 1986; 35: 1130–1142.PubMedCrossRefGoogle Scholar
  22. 22.
    Kanwar YS, Rosenzweig LJ, Linker A, Jakubowski ML. Decreased de novo synthesis of glomerular proteoglycans in diabetes. Proc Natl Acad Sci USA 1983; 80: 2272–2275.PubMedCrossRefGoogle Scholar
  23. 23.
    Cohen MP, Surma ML. Effect of diabetes on in vivo metabolism of 35S-labelled glomerular basement membrane. Diabetes 1984; 33: 8–12.PubMedCrossRefGoogle Scholar
  24. 24.
    Klein DJ, Oegema TR, Brown DM. Release of glomerular heparan-35SO4 proteoglycan by heparin from glomeruli of streptozotocin-induced diabetic rats. Diabetes 1989; 38: 130–139.PubMedCrossRefGoogle Scholar
  25. 25.
    Wu V-Y, Wilson B, Cohen MP. Disturbances in glomerular basement membrane glycosaminoglycans in experimental diabetes. Diabetes 1987; 36: 679–683.PubMedCrossRefGoogle Scholar
  26. 26.
    Templeton DM. Retention of glomerular basement membrane proteoglycans accompanying loss of anionic site staining in experimental diabetes. Lab Invest 1989; 61: 202–211.PubMedGoogle Scholar
  27. 27.
    Cohen MP, Klepser H, Wu V-Y. Undersulfation of glomerular basement membrane heparan sulfate in experimental diabetes and lack of correction with aldose reductase inhibition. Diabetes 1988; 37: 1324–1327.PubMedCrossRefGoogle Scholar
  28. 28.
    Fukui M, Nakamura T, Ebihara I, Shirato I, Tomino Y, Koide H. ECM gene expression and its modulation by insulin in diabetic rats. Diabetes 1992; 41: 1520–1527.PubMedCrossRefGoogle Scholar
  29. 29.
    Kofoed-Enevoldsen A, Noonan D, Deckert T. Diabetes mellitus induced inhibition of glucosaminyl N-deacetylase — effect of short-term blood glucose control. Diabetologia 1993; 36: 310–315.PubMedCrossRefGoogle Scholar
  30. 30.
    Kashihara N, Watanabe Y, Makino H, Wallner EI, Kanwar Y. Selective decreased de novo synthesis of glomerular proteoglycans under the influence of reactive oxygen species. Proc Natl Acad Sci USA 1992; 89: 6309–6313.PubMedCrossRefGoogle Scholar
  31. 31.
    Olgemöller B, Schwaabe S, Gerbitz KD, Schleicher ED. Elevated glucose decreases the content of a basement membrane associated heparan sulphate proteoglycan in proliferating cultured porcine mesangial cells. Diabetologia 1992; 35: 183–186.PubMedCrossRefGoogle Scholar
  32. 32.
    Doi T, Vlassara H, Kirstein M, Yamada Y, Striker GE, Striker LJ. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glysosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 1992; 89: 2873–2877.PubMedCrossRefGoogle Scholar
  33. 33.
    Cagliero E, Roth T, Roy S, Lorenzi M. Characteristics and mechanisms of high-glucose-induced overexpression of basement membrane components in cultures human endothelial cells. Diabetes 1991; 40: 102–110.PubMedCrossRefGoogle Scholar
  34. 34.
    Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, Haverty TP. High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule. Am J Physiol 1990; 259: F704–F714.PubMedGoogle Scholar
  35. 35.
    Shankland SJ, Scholey JW. Expression of transforming growth factor-ß1 during diabetic renal hypertrophy. Kidney Int 1994; 46: 430–442.PubMedCrossRefGoogle Scholar
  36. 36.
    Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti. Natural inhibitor of transforming growth factor-ß protects against scarring in experimental kidney disease. Nature 1992; 360:361–364.PubMedCrossRefGoogle Scholar
  37. 37.
    Mulder M, Lombardi P, Jansen H, van Berkel TJC, Frants RR, Havekes LM. Heparan sulphate proteoglycans are involved in the lipoprotein lipase-mediated enhancement of the cellular binding of very low density and low density lipoproteins. Biochem Biophys Res Commun 1992; 185: 582–587.PubMedCrossRefGoogle Scholar
  38. 38.
    Sudhalter J, Folkman J, Svahn CM, Bergendal K, D’Amore PA. Importance of size, sulfatation and anticoagulant activity in the potentiation of acidic fibroblast growth factor by heparin. J Biol Chem 1989; 264: 6892–6897.PubMedGoogle Scholar
  39. 39.
    Turnbull JE, Fernig DG, Ke Y, Wilkinson MC, Gallagher JT. Identification of the basic fibroblast growth factor binding sequence in fibroblast heparan sulfate. J Biol Chem 1992; 267: 10337–10341.PubMedGoogle Scholar
  40. 40.
    Deckert T, Jensen T, Feldt-Rasmussen B, Kofoed-Enevoldsen A, Borch-Johnsen K, Stender S. Albuminuria a risk marker of atherosclerosis in insulin dependent diabetes mellitus. Cardiovasc Risk Factors 1991; 1: 347–360.Google Scholar
  41. 41.
    Deckert T, Kofoed-Enevoldsen A, Nørgaard K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen T. Microalbuminuria — implications for micro and macrovascular disease. Diabetes Care 1992; 15:1181–1191.PubMedCrossRefGoogle Scholar
  42. 42.
    Gruden G, Cavallo-Perin P, Bazzan M, Stella S, Bruno A, Pagano G. Haemostatic alterations in microalbuminuric insulin-dependent diabetic patients (Abstract). Diabetologia 1993; 36: Suppl. 1: A215.Google Scholar
  43. 43.
    Myrup B, Rossing P, Jensen T, Gram J, Kluft C, Jespersen J. Prothrombin fragment 1+2, a marker of thrombin formation, is related to transcapillary escape rate of albumin in insulin-dependent diabetic patients (Abstract). Diabetologia 1993; 36: Suppl. 1: A71.Google Scholar
  44. 44.
    Kofoed-Enevoldsen A, Bent-Hansen L, Deckert T. Transcapillary filtration of plasma protein in long-term type 1 (insulin-dependent) diabetic patients. Scand J Clin Lab Invest 1992; 52: 591–597.PubMedCrossRefGoogle Scholar
  45. 45.
    Bent-Hansen L, Feldt-Rasmussen B, Kverneland A, Deckert T. Plasma disappearance of glycated and non-glycated albumin in type 1 (insulin-dependent) diabetes mellitus — evidence for charge dependent alterations of the plasma to lymph pathway. Diabetologia 1993; 36: 361–363.PubMedCrossRefGoogle Scholar
  46. 46.
    Kjellén L, Bielefeld D, Höök M. Reduced sulfatation of liver heparan sulfate in experimentally diabetic rats. Diabetes 1983; 32: 337–342.PubMedCrossRefGoogle Scholar
  47. 47.
    Unger E, Pettersson I, Eriksson UJ, Lindahl U, Kjellén L. Decreased activity of the heparan sulfate modifying enzyme glucosaminyl N-deacatylase in hepatocytes from streptozotocin-diabetic rats. J Biol Chem 1991; 266: 8671–8674.PubMedGoogle Scholar
  48. 48.
    Kofoed-Enevoldsen A, Eriksson UJ. Inhibition of N-acetylheparosan deacetylase in diabetic rats. Diabetes 1991; 40: 1449–1452.PubMedCrossRefGoogle Scholar
  49. 49.
    Kofoed-Enevoldsen A. Inhibition of glomerular glucosaminyl N-deacetylase in diabetic rats. Kidney Int 1992;41:763–767.PubMedCrossRefGoogle Scholar
  50. 50.
    Kofoed-Enevoldsen A, Kotinis A, Deckert T. Poor metabolic control decreases n-deacetylase activity type-1 diabetic-patients (Abstract). Diabetologia 1994; 37: Suppl. 1: A3.CrossRefGoogle Scholar
  51. 51.
    Kofoed-Enevoldsen A, Petersen JS, Deckert T. Glucosaminyl N-deacetylase in cultured fibroblasts — comparison of patients with and without diabetic nephropathy, and identification of a possible mechanism for diabetes-induced N-deacetylase inhibition. Diabetologia 1993; 36: 536–540.PubMedCrossRefGoogle Scholar
  52. 52.
    Walkenbach RJ, Hazen R, Larner J. Reversible inhibition of cyclic AMP-dependent protein kinase by insulin. Mol Cell Biochem 1978; 19: 31–41.PubMedGoogle Scholar
  53. 53.
    Kida Y, Nyomba BL, Bogardus C, Mott DM. Defective insulin response of cyclic adenosine monophosphate-dependent protein kinase in insulin resistant humans. J Clin Invest 1991; 87: 673–679.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Trevisan R, Nosadini R, Fioretto P, Semplicini A, Donadon V, Doria A et al. Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport. Kidney Int 1992;41:855–861.PubMedCrossRefGoogle Scholar
  55. 55.
    Myrup B, Hansen PM, Jensen T, Kofoed-Enevoldsen A, Feldt-Rasmussen B, Gram J, Kluft C, Jespersen J, Deckert T. Effect of low-dose heparin on urinary albumin excretion in insulin-dependent diabetes mellitus. Lancet 1995; 345: 421–422.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Allan Kofoed-Enevoldsen
    • 1
  1. 1.Steno Diabetes CenterGentofteDenmark

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