The Role of Growth Factors in Diabetic Kidney Disease

  • Allan Flyvbjerg
  • Henning Grønbæk
  • Martin Bak
  • Birgitte Nielsen
  • Thora Christiansen
  • Ida Vogel
  • Hans Ørskov


Growth factors have attracted attention in several areas of diabetes research including conceivable effects on the renal changes seen in experimental and human diabetes. In our review article published in The Kidney and Hypertension in Diabetes Mellitus, Second Edition, 1994 we covered the published evidence for a connection between changes in various growth factors (growth hormone (GH), insulin-like growth factors (IGFs), epidermal growth factor (EGF), transforming growth factor β (TGF-β), platelet derived growth factor (PDGF), tumor necrosis factor α (TNF-α) and fibroblastic growth factors (FGFs)) and the development of renal changes in diabetes. Almost every month there are several new papers on the possible relationship between growth factors and the development of diabetic nephropathy, which makes it progressively more difficult to write an ‘up-to-date’ review on the topic, and not all papers can be discussed in detail here.


Urinary Albumin Excretion Diabetic Kidney Disease Diabetes Induction Renal Hypertrophy Octreotide Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Flyvbjerg A. The growth hormone/insulin-like growth factor axis in the kidney: Aspects in relation to chronic renal failure. J Pediatr Endocrinol 1994; 7: 85–92.PubMedGoogle Scholar
  2. 2.
    Flyvbjerg A, Landau D, Domene H, Hernandez L, Grønbök H, LeRoith D. The role of growth hormone, insulin-like growth factors (IGFs), and IGF-Binding proteins in experimental diabetic kidney disease. Metabolism 1995; 44: 67–71.PubMedCrossRefGoogle Scholar
  3. 3.
    Bortz JD, Rotwein P, DeVol D, Bechtel PJ, Hansen VA, Hammerman MR. Focal expression of insulin-like growth factor I in rat kidney collecting duct. J Cell Biol 1988; 107: 811–819.PubMedCrossRefGoogle Scholar
  4. 4.
    Flyvbjerg A, Marshall SM, Frystyk J, Rasch R, Bornfeldt KE, Arnqvist H, Jensen PK, Pallesen G, Ørskov H. Insulin-like growth factor I in initial renal hypertrophy in potassium-depleted rats. Am J Physiol 1992; 262: F1023–F1031.PubMedGoogle Scholar
  5. 5.
    Landau D, Chin E, Bondy C, Domene H, Roberts CT, Grønbæk H, Flyvbjerg A, LeRoith D. Expression of insulin-like growth factor binding proteins in the rat kidney: Effects of long-term diabetes. Endocrinology 1995; 136: 1835–1842.PubMedCrossRefGoogle Scholar
  6. 6.
    Arnqvist HJ, Ballermann BJ, King GL. Receptors for and effects of insulin and IGF-I in rat glomerular mesangial cells. Am J Physiol 1988; 254: C411–C416.PubMedGoogle Scholar
  7. 7.
    Pillion DJ, Haskell JF, Meezan E. Distinct receptors for insulin-like growth factor I in rat renal glomeruli and tubules. Am J Physiol 1988; 255: E504–E512.PubMedGoogle Scholar
  8. 8.
    Chin E, Bondy C. Insulin-like growth factor system gene expression in the human kidney. J Clin Endocrinol Metab 1992; 75: 962–968.PubMedCrossRefGoogle Scholar
  9. 9.
    Shimasaki S, Shimonaka M, Zhang HP, Ling N. Identification of five different insulin-like growth factor binding proteins (IGFBPs) from adult rat serum and molecular cloning of a novel IGFBP-5 in rat and human. J Biol Chem 1991; 266: 10646–10653.PubMedGoogle Scholar
  10. 10.
    Shimasaki S, Gao L, Shimonaka M, Ling N. Isolation and molecular cloning of insulin-like growth factor binding protein 6. Mol Endocrinol 1991; 5: 938–948.PubMedCrossRefGoogle Scholar
  11. 11.
    Flyvbjerg A, Thorlacius-Ussing O, Næraa R, Ingerslev J, Ørskov H. Kidney tissue somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologia 1988; 31: 310–314.PubMedGoogle Scholar
  12. 12.
    Flyvbjerg A, Frystyk J, Thorlacius-Ussing O, Ørskov H. Somatostatin analogue administration prevents increase in kidney somatomedin C and initial renal growth in diabetic and uninephrectomized rats. Diabetologia 1989; 32: 261–265.PubMedCrossRefGoogle Scholar
  13. 13.
    Flyvbjerg A, Bornfeldt KE, Marshall SM, Arnqvist HJ, Ørskov H. Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats. Diabetologia 1990; 33: 334–338.PubMedCrossRefGoogle Scholar
  14. 14.
    Flyvbjerg A, Orskov H. Kidney tissue insulin-like growth factor I and initial renal growth in diabetic rats: relation to severity of diabetes. Acta Endocrinol (Copenh) 1990; 122: 374–378.Google Scholar
  15. 15.
    Werner H, Shen Orr Z, Stannard B, Burguera B, Roberts CT Jr, LeRoith D. Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene expression in kidney. Diabetes 1990; 39: 1490–1497.PubMedCrossRefGoogle Scholar
  16. 16.
    Bornfeldt KE, Arnqvist HJ, Enberg B, Mathews LS, Norstedt G. Regulation of insulin-like growth factor I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues. J Endocrinol 1989; 122: 651–656.PubMedCrossRefGoogle Scholar
  17. 17.
    Bach LA, Stevenson JL, Allen TJ, Jerums G, Herington AC. Kidney insulin-like growth factor-I mRNA levels are increased in postpubertal diabetic rats. J Endocrinol 1991; 129: 5–10.PubMedCrossRefGoogle Scholar
  18. 18.
    Marshall SM, Flyvbjerg A, Frystyk J, Korsgaard L, Ørskov H. Renal insulin-like growth factor I and growth hormone receptor binding in experimental diabetes and after unilateral nephrectomy in the rat. Diabetologia 1991; 34: 632–639.PubMedCrossRefGoogle Scholar
  19. 19.
    Flyvbjerg A, Kessler U, Dorka B, Funk B, Ørskov H, Kiess W. Transient increase in renal insulin-like growth factor binding proteins during initial kidney hypertrophy in experimental diabetes in rats. Diabetologia 1992; 35: 589–593.PubMedCrossRefGoogle Scholar
  20. 20.
    Steer KA, Sochor M, Kunjara S, Doepfner W, McLean P. The effect of a somatostatin analogue (SMS 201-995) on the concentration of phosphoribosyl pyrophosphate and the activity of the pentose phosphate pathway in the early renal hypertrophy of experimental diabetes in the rat. Biochem Med Metab Biol 1988; 39: 226–233.PubMedCrossRefGoogle Scholar
  21. 21.
    Grønbæk H, Nielsen B, Frystyk J, Ørskov H, Flyvbjerg A. Effect of octreotide on experimental diabetic renal and glomerular growth: Importance of early intervention. J Endocrinol 1995; 147: 95–102.PubMedCrossRefGoogle Scholar
  22. 22.
    Grønbæk H, Nielsen B, Østerby R, Harris AG, Ørskov H, Flyvbjerg A. Effect of octreotide and insulin on manifest renal and glomerular hypertrophy and urinary albumin excretion in long-term experimental diabetes in rats. Diabetologia 1995; 38: 135–144.PubMedCrossRefGoogle Scholar
  23. 23.
    Grønbæk H, Nielsen B, Frystyk J, Flyvbjerg A, Ørskov H. Effect of lanreotide, a somatostatin analogue, on diabetic renal hypertrophy, kidney and serum IGF-I and IGF binding proteins. Experimental Nephrology 1996; in press.Google Scholar
  24. 24.
    Weiss O, Rubinger D, Nephesh I, Moshe R, Raz I. The influence of octreotide on IGF system gene expression in the kidney of diabetic rats (Abstract). Diabetologia 1995; 38: A206.Google Scholar
  25. 25.
    Flyvbjerg A, Marshall SM, Frystyk J, Hansen KW, Harris AG, Ørskov H. Octreotide administration in diabetic rats: effects on renal hypertrophy and urinary albumin excretion. Kidney Int 1992; 41: 805–812.PubMedCrossRefGoogle Scholar
  26. 26.
    Iwasaki S. Octreotide suppresses the kidney weight and glomerular hypertrophy in diabetic rats. Nippon Jinzo Gakkai Shi 1993; 35: 247–255.PubMedGoogle Scholar
  27. 27.
    Muntzel M, Hannedouche T, Niesor R, Noel LH, Souberbielle JC, Lacour B, Drueke T. Long-term effects of a somatostatin analogue on renal haemodynamics and hypertrophy in diabetic rats. Clin Sci 1992; 83: 575–581.PubMedGoogle Scholar
  28. 28.
    Igarashi K, Ito S, Shibata A. Effect of a somatostatin analogue (SMS 201–995) on urinary albumin excretion in streptozotocin-induced diabetic rats. J Japan Diab Soc 1990; 33: 531–538.Google Scholar
  29. 29.
    Igarashi K, Nakazawa A, Tani N, Yamazaki M, Ito S, Shibata A. Effect of a somatostatin analogue (SMS 201–995) on renal function and excretion in diabetic rats. J Diabetic Compl 1991; 5: 181–183.CrossRefGoogle Scholar
  30. 30.
    Grønbæk H, Vogel I, Lancranjan I, Flyvbjerg A, Ørskov H. Effect of octreotide, captopril, or insulin on manifest long-term experimental diabetic renal changes (Abstract). Diabetologia 1995; 38: A206.CrossRefGoogle Scholar
  31. 31.
    Vora J, Owens DR, Luzio SD, Atiea J, Ryder R, Hayes TM. Renal response to intravenous somatostatin in insulin-dependent diabetic patients and normal subjects. J Clin Endocrinol Metab 1987; 64: 975–979.PubMedCrossRefGoogle Scholar
  32. 32.
    Pedersen MM, Christensen SE, Christiansen JS, Pedersen EB, Mogensen CE, Ørskov H. Acute effects of a somatostatin analogue on kidney function in type 1 diabetic patients. Diabetic Med 1990; 7: 304–309.PubMedCrossRefGoogle Scholar
  33. 33.
    Krempf M, Ranganathan S, Remy JP, Charbonnel B, Guillon J. Effect of a long acting somatostatin analogue (SMS 201–1995) on high glomerular filtration rate in insulin dependent diabetic patients. Int J Clin Pharmacol Ther Toxicol 1990; 28: 309–311.PubMedGoogle Scholar
  34. 34.
    Serri O, Beauregard H, Brazeau P, Abribat T, Lambert J, Harris A, Vachon L. Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes. JAMA 1991; 265: 888–892.PubMedCrossRefGoogle Scholar
  35. 35.
    Nakamura T, Fukui M, Ebihara E, Osada S, Nagaoka I, Tomino Y, Koide H. mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 1993; 42: 450–456.PubMedCrossRefGoogle Scholar
  36. 36.
    Ziyadeh FN, Chen Y, Davila A, Goldfarb S. Self limited stimulation of mesangial cell growth in high glucose: autocrine activation of TGF-β reduces proliferation but increases mesangial matrix. Kidney Int 1992; 42: 647–656.PubMedCrossRefGoogle Scholar
  37. 37.
    Choi ME, Eung-Gook K, Ballerman BJ. Rat mesangial cell hypertrophy in response to transforming growth factor β1. Kidney Int 1993; 44: 948–958.PubMedCrossRefGoogle Scholar
  38. 38.
    Ziyadeh FN, Snipes ER, Watanabe M, Alvarey 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
  39. 39.
    Rocco MV, Chen Y, Goldfarb S, Ziyadeh FN. Elevated glucose stimulates TGF-β gene expression and bioactivity in proximal tubules. Kidney Int 1992; 41: 107–114.PubMedCrossRefGoogle Scholar
  40. 40.
    Nakamura T, Miller D, Rouslahti E, Border WA. Production of extracellular matrix by glomerular epithelial cells is regulated by transforming growth factor β1. Kidney Int 1992; 41: 1213–1221.PubMedCrossRefGoogle Scholar
  41. 41.
    Humes HD, Nakamura T, Cieslinski DA, Miller D, Emmons RV, Border WA. Role of protoglycans and cytoskeleton in the effects of TGF-β1 on renal proximal tubule cells. Kidney Int 1993; 43: 575–584.PubMedCrossRefGoogle Scholar
  42. 42.
    Roberts AB, McCune BK, Sporn MB. TGF-β1: Regulation of extracellular matrix. Kidney Int 1992; 41: 557–559.PubMedCrossRefGoogle Scholar
  43. 43.
    Davies M, Thomas GJ, Martin J, Lovett DH. The purification and characterisation of a glomerular basement membrane degrading neutral proteinase from the rat mesangial cells. Biochem J 1988; 251: 419–425.PubMedGoogle Scholar
  44. 44.
    Edwards DR, Murphy G, Reynolds JJ, Whitman SE, Docherty AJP, Angel P, Heath JK. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor (Abstract). EMBO J 1987; 6: 1899.PubMedGoogle Scholar
  45. 45.
    Lovett DH, Marti HP, Martin J, Grond J, Kashfarian DH. Transforming growth factor β1 stimulates mesangial cell synthesis of the 72 kD type IV collagenase independent of TIMP-1 (Abstract). J Am Soc Nephrol 1991; 1:578.Google Scholar
  46. 46.
    Okuda S, Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-β and proteoglycan production in experimental glomerulonephritis. Possible role in expansion of the mesangial matrix. J Clin Invest 1990; 86: 453–462.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti. Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1. Nature 1990; 346: 371–374.PubMedCrossRefGoogle Scholar
  48. 48.
    Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti. Natural inhibitor of transforming growth factor-β protects against scarring in experimental kidney disease. Nature 1992; 360: 361–364.PubMedCrossRefGoogle Scholar
  49. 49.
    Ziyadeh FN, Sharma K, Ricksen N, Wolf G. Stimulation of callagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor β. J Clin Invest 1994; 93: 536–542.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Shankland SJ, Scholey JW. Expression of transforming grwoth factor β1 during diabetic renal hypertrophy. Kidney Int 1994; 46: 430–442.PubMedCrossRefGoogle Scholar
  51. 51.
    Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, Border WA. Expression of transforming growth factor is elevated in human and experimental diabetic glomerulopathy. Proc Natl Acad Sci USA 1993; 90: 1814–1818.PubMedCrossRefGoogle Scholar
  52. 52.
    Sharma K, Jin Y, Guo J, Ziyadeh FN. Neutralization of TGF-β by anti-TGF-β antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 1996; 45: 522–530.PubMedCrossRefGoogle Scholar
  53. 53.
    Korpinen E, Teppo A-M, Groop H-H, Fagerudd J, Åkerblom HK, Varala O. Elevated levels of urinary transforming growth factor-ßl in young IDDM patients (Abstract). Diabetologia 1996; 39: Suppl. 1: A293.Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Allan Flyvbjerg
    • 1
  • Henning Grønbæk
    • 1
  • Martin Bak
    • 1
  • Birgitte Nielsen
    • 1
  • Thora Christiansen
    • 1
  • Ida Vogel
    • 1
  • Hans Ørskov
    • 1
  1. 1.Medical Research Laboratories, Institute of Experimental Clinical ResearchUniversity Hospital, Aarhus KommunehospitalAarhusDenmark

Personalised recommendations