Proteinuria and Interstitial Fibrogenesis in Diabetic Nephropathy

  • Raimund Hirschberg
Part of the Contemporary Diabetes book series (CDI)


In chronic renal glomerular diseases the degree of interstitial fibrosis determines enal failure and the rate of progression toward end-stage renal disease. This relationship etween renal insufficiency and interstitial fibrosis has also emerged in the most ommon single disease entity causing renal failure with the need for chronic renal eplacement therapy, namely diabetic nephropathy (DN) (1,2)


Diabetic Nephropathy Hepatocyte Growth Factor Tubular Cell Connective Tissue Growth Factor Interstitial Fibrosis 
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.
    Bohle A, Wehrmann M, Bogenschutz O, Batz C, Muller CA, Muller GA. The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract 1991;187:251–259.PubMedGoogle Scholar
  2. 2.
    Taft JL, Nolan CJ, Yeung SP, Hewitson TD, Martin FI. Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria. Diabetes 1994;43:1046–1051.PubMedCrossRefGoogle Scholar
  3. 3.
    Peterson JC, Adler S, Burkart JM, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Int Med 1995;123:754–762.PubMedGoogle Scholar
  4. 4.
    Ruggenenti P, Perna A, Mosconi L, et al. Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney Int Suppl 1997;63:S54–S57.PubMedGoogle Scholar
  5. 5.
    Narita T, Koshimura J, Suzuki K, et al. Effects of short-term glycemic control, low protein diet and administration of enalapril on renal hemodynamics and protein permselectivity in type 2 diabetic patients with microalbuminuria. Tohoku J Exp Med 1999;189:117–133.PubMedCrossRefGoogle Scholar
  6. 6.
    Narita T, Sasaki H, Hosoba M, et al. Parallel increase in urinary excretion rates of immunoglobulin G, ceruloplasmin, transferrin, and orosomucoid in normoalbuminuric type 2 diabetic patients. Diabetes Care 2004;27:1176–1181.PubMedCrossRefGoogle Scholar
  7. 7.
    Zoja C, Morigi M, Remuzzi G. Proteinuria and phenotypic change of proximal tubular cells. J Am Soc Nephrol 2003;14(1):S36–S41.PubMedCrossRefGoogle Scholar
  8. 8.
    Donadelli R, Abbate M, Zanchi C, et al. Protein traffic activates NF-kB gene signaling and promotes MCP-1-dependent interstitial inflammation. Am J Kidney Dis 2000;36:1226–1241.PubMedGoogle Scholar
  9. 9.
    Donadelli R, Zanchi C, Morigi M, et al. Protein overload induces fractalkine upregulation in proximal tubular cells through nuclear factor kappaB-and p38 mitogen-activated protein kinase-dependent pathways. J Am Soc Nephrol 2003;14:2436–2446.PubMedCrossRefGoogle Scholar
  10. 10.
    Zoja C, Donadelli R, Colleoni S, et al. Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation. Kidney International 1998;53:1608–1615.PubMedCrossRefGoogle Scholar
  11. 11.
    Hanada T, Yoshimura A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 2002;13:413–421.PubMedCrossRefGoogle Scholar
  12. 12.
    Miyajima A, Kosaka T, Seta K, Asano T, Umezawa K, Hayakawa M. Novel nuclear factor kappa B activation inhibitor prevents inflammatory injury in unilateral ureteral obstruction. J Urol 2003;169:1559–1563.PubMedCrossRefGoogle Scholar
  13. 13.
    Burton CJ, Combe C, Walls J, Harris KP. Fibronectin production by human tubular cells: the effect of apical protein. Kidney Int 1996;50:760–767.PubMedCrossRefGoogle Scholar
  14. 14.
    Burton CJ, Combe C, Walls J, Harris KP. Secretion of chemokines and cytokines by human tubular epithelial cells in response to proteins. Nephrol Dial Transplant 1999;14:2628–2633.PubMedCrossRefGoogle Scholar
  15. 15.
    Thomas ME, Brunskill NJ, Harris KP, et al. Proteinuria induces tubular cell turnover: A potential mechanism for tubular atrophy. Kidney Int 1999;55:890–898.PubMedCrossRefGoogle Scholar
  16. 16.
    Schreiner GF. Renal toxicity of albumin and other lipoproteins. Curr Opin Nephrol Hypertens 1995;4:369–373.PubMedCrossRefGoogle Scholar
  17. 17.
    Arici M, Brown J, Harris K, Walls J, Brunskill N. Albumin induced changes in human proximal tubular cell function are dependent on its fatty acid content. J Am Soc Nephrol 1999;10:654“abstract.&rdquoGoogle Scholar
  18. 18.
    Arici M, Brown J, Williams M, Harris KP, Walls J, Brunskill NJ. Fatty acids carried on albumin modulate proximal tubular cell fibronectin production: a role for protein kinase C. Nephrol Dial Transplant 2002;17:1751–1757.PubMedCrossRefGoogle Scholar
  19. 19.
    Arici M, Chana R, Lewington A, Brown J, Brunskill NJ. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol 2003;14:17–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Hirschberg R. Bioactivity of glomerular ultrafiltrate during heavy proteinuria may contribute to renal tubulo-interstitial lesions: evidence for a role for insulin-like growth factor I. J Clin Invest 1996;98:116–124.PubMedCrossRefGoogle Scholar
  21. 21.
    Hammerman MR, Rogers S. Distribution of IGF receptors in the plasma membrane of proximal tubular cells. Am J Physiol 1987;253:F841–F847.PubMedGoogle Scholar
  22. 22.
    Quigley R, Baum M. Effects of growth hormone and insulin-like growth factor I on rabbit proximal convoluted tubule transport. J Clin Invest 1991;88:368–374.PubMedGoogle Scholar
  23. 23.
    Hirschberg R, Kaysen GA. Insulin-like growth factor I and its binding proteins in the experimental nephrotic syndrome. Endocrinology 1995;136:1565–1571.PubMedCrossRefGoogle Scholar
  24. 24.
    Nyengaard JR, Flyvbjerg A, Rasch R. The impact of renal growth, regression and regrowth in experimental diabetes mellitus on number and size of proximal and distal tubular cells in the rat kidney. Diabetologia 1993;36:1126–1131.PubMedCrossRefGoogle Scholar
  25. 25.
    Rasch R. Tubular lesions in streptozotocin-diabetic rats. Diabetologia 1984;27:32–37.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang S, LaPage J, Hirschberg R. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int 2000;57:1002–1014.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang X, Yang J, Li Y, Liu Y. Both Sp1 and Smad participate in mediating TGF-beta1-induced HGF receptor expression in renal epithelial cells. Am J Physiol Renal Physiol 2005;288:F16–F26.PubMedCrossRefGoogle Scholar
  28. 28.
    Wang S, Hirschberg R. Growth factor ultrafiltration in experimental diabetic nephropathy contributes to interstitial fibrosis. Am J Physiol 2000;278:F554–F560.Google Scholar
  29. 29.
    Roberts AB. Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 1998;24:111–119.PubMedCrossRefGoogle Scholar
  30. 30.
    Ando T, Okuda S, Yanagida T, Fujishima M. Localization of TGF-beta and its receptors in the kidney. Miner Electrolyte Metab 1998;24:149–153.PubMedCrossRefGoogle Scholar
  31. 31.
    Honkanen E, Teppo AM, Tornroth T, Groop PH, Gronhagen-Riska C. Urinary transforming growth factor-beta 1 in membranous glomerulonephritis. Nephrol Dial Transplant 1997;12:2562–2568.PubMedCrossRefGoogle Scholar
  32. 32.
    Sato H, Iwano M, Akai Y, et al. Increased excretion of urinary transforming growth factor beta 1 in patients with diabetic nephropathy. Am J Nephrol 1998;18:490–494.PubMedCrossRefGoogle Scholar
  33. 33.
    Song JH, Lee SW, Suh JH, et al. The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy. Clin Nephrol 2003;60:318–326.PubMedGoogle Scholar
  34. 34.
    Johnson DW, Saunders HJ, Baxter RC, Field MJ, Pollock CA. Paracrine stimulation of human renal fibroblasts by proximal tubule cells. Kidney Int 1998;54:747–757.PubMedCrossRefGoogle Scholar
  35. 35.
    Tang WW, Ulich TR, Lacey DL, et al. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 1996;148:1169–1180.PubMedGoogle Scholar
  36. 36.
    Grotendorst GR, Rahmanie H, Duncan MR. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation. FASEB J 2004;18:469–479.PubMedCrossRefGoogle Scholar
  37. 37.
    Bradham DM, Igarashi A, Potter RL, Grotendorst GR. Connective tissue growth factor: a cysteinerich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol 1991;114:1285–1294.PubMedCrossRefGoogle Scholar
  38. 38.
    Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ 1996;7:469–480.PubMedGoogle Scholar
  39. 39.
    Wang S, Denichilo M, Brubaker C, Hirschberg R. Connective tissue growth factor in tubulointerstitial injury of diabetic nephropathy. Kidney Int 2001;60:96–105.PubMedCrossRefGoogle Scholar
  40. 40.
    Yang DH, Kim HS, Wilson EM, Rosenfeld RG, Oh Y. Identification of glycosylated 38-kDa connective tissue growth factor (IGFBP-related protein 2) and proteolytic fragments in human biological fluids, and up-regulation of IGFBP-rP2 expression by TGF-beta in Hs578T human breast cancer cells. J Clin Endocrinol Metab 1998;83:2593–2596.PubMedCrossRefGoogle Scholar
  41. 41.
    Kim HS, Nagalla SR, Oh Y, Wilson E, Roberts CT Jr, Rosenfeld RG. Identification of a family of lowaffinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc Natl Acad Sci USA 1997;94:12,981–12,986.PubMedCrossRefGoogle Scholar
  42. 42.
    Segarini PR, Nesbitt JE, Li D, Hays LG, Yates JR 3rd, Carmichael DF. The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor is a receptor for connective tissue growth factor. J Biol Chem 2001;276:40,659–40,667.PubMedCrossRefGoogle Scholar
  43. 43.
    Lam S, van der Geest RN, Verhagen NA, et al. Connective tissue growth factor and igf-I are produced by human renal fibroblasts and cooperate in the induction of collagen production by high glucose. Diabetes 2003;52:2975–2983.PubMedCrossRefGoogle Scholar
  44. 44.
    Martin P. Wound healing—aiming for perfect skin regeneration. Science 1997;276:75–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Wada T, Furuichi K, Sakai N, et al. Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int 2000;58:1492–1499.PubMedCrossRefGoogle Scholar
  46. 46.
    Amann B, Tinzmann R, Angelkort B. ACE inhibitors improve diabetic nephropathy through suppression of renal MCP-1. Diabetes Care 2003;26:2421–2425.PubMedCrossRefGoogle Scholar
  47. 47.
    Rovin BH, Doe N, Tan LC. Monocyte chemoattractant protein-1 levels in patients with glomerular disease. Am J Kidney Dis 1996;27:640–646.PubMedGoogle Scholar
  48. 48.
    Morii T, Fujita H, Narita T, et al. Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J Diabetes Complications 2003;17:11–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Mezzano S, Aros C, Droguett A, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 2004;19:2505–2512.PubMedCrossRefGoogle Scholar
  50. 50.
    Wang S, Wilkes MC, Leof EB, Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. FASEB J 2005;19:1–11.PubMedCrossRefGoogle Scholar
  51. 51.
    Lassila M, Jandeleit-Dahm K, Seah KK, et al. Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol 2005;16:363–373.PubMedCrossRefGoogle Scholar
  52. 52.
    Massague J, Kelly B, Mottola C. Stimulation by insulin-like growth factors is required for cellular transformation by type beta transforming growth factor. J Biol Chem 1985;260:4551–4554.PubMedGoogle Scholar
  53. 53.
    Essawy M, Soylemezoglu O, Muchaneta-Kubara EC, Shortland J, Brown CB, elNahas AM. Myofibroblasts and the progression of diabetic nephropathy. Nephrol Dial Transplant 1997;12:43–50.PubMedCrossRefGoogle Scholar
  54. 54.
    Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 2003;112:1776–1784.PubMedCrossRefGoogle Scholar
  55. 55.
    Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003;12:25–29.PubMedCrossRefGoogle Scholar
  56. 56.
    Hashimoto N, Jin H, Liu T, Chensue SW, Phan SH. Bone marrow-derived progenitor cells in pulmonary fibrosis. J Clin Invest 2004;113:243–252.PubMedCrossRefGoogle Scholar
  57. 57.
    Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 2002;110:341–350.PubMedCrossRefGoogle Scholar
  58. 58.
    Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869.PubMedCrossRefGoogle Scholar
  59. 59.
    Park HC, Xu ZG, Choi S, et al. Effect of losartan and amlodipine on proteinuria and transforming growth factor-beta1 in patients with IgA nephropathy. Nephrol Dial Transplant 2003;18:1115–1121.PubMedCrossRefGoogle Scholar
  60. 60.
    Andersen S, Brochner-Mortensen J, Parving HH. Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria. Diabetes Care 2003;26:3296–3302.PubMedCrossRefGoogle Scholar
  61. 61.
    Ruilope LM, Segura J. Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther 2003;25:3044–3064.PubMedCrossRefGoogle Scholar
  62. 62.
    Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361:117–124.PubMedCrossRefGoogle Scholar
  63. 63.
    Shimizu H, Maruyama S, Yuzawa Y, et al. Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J Am Soc Nephrol 2003;14:1496–505.PubMedCrossRefGoogle Scholar
  64. 64.
    Takase O, Hirahashi J, Takayanagi A, et al. Gene transfer of truncated IkappaBalpha prevents tubulointerstitial injury. Kidney Int 2003;63:501–513.PubMedCrossRefGoogle Scholar
  65. 65.
    Rajkumar SV, Richardson PG, Hideshima T, Anderson KC. Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 2005;23:630–639.PubMedCrossRefGoogle Scholar
  66. 66.
    Hideshima T, Chauhan D, Richardson P, et al. NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 2002;277:16,639–16,347.PubMedCrossRefGoogle Scholar
  67. 67.
    Liu Y. Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action. Am J Physiol Renal Physiol 2004;287:F7–F16.PubMedCrossRefGoogle Scholar
  68. 68.
    Dai C, Liu Y. Hepatocyte growth factor antagonizes the profibrotic action of TGF-beta1 in mesangial cells by stabilizing Smad transcriptional corepressor TGIF. J Am Soc Nephrol 2004;15:1402–1412.PubMedCrossRefGoogle Scholar
  69. 69.
    Dai C, Yang J, Bastacky S, Xia J, Li Y, Liu Y. Intravenous administration of hepatocyte growth factor gene ameliorates diabetic nephropathy in mice. J Am Soc Nephrol 2004;15:2637–2647.PubMedCrossRefGoogle Scholar
  70. 70.
    Inoue T, Okada H, Kobayashi T, et al. Hepatocyte growth factor counteracts transforming growth factorbeta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. FASEB J 2003;17:268–270.PubMedGoogle Scholar
  71. 71.
    Cruzado JM, Lloberas N, Torras J, et al. Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats. Diabetes 2004;53:1119–1127.PubMedCrossRefGoogle Scholar
  72. 72.
    Wang S, LaPage J, Hirschberg R. Loss of tubular bone morphogenetic protein-7 (BMP7) in diabetic nephropathy. J Am Soc Nephrol 2001;12:2392–2399.PubMedGoogle Scholar
  73. 73.
    Wang S, Hirschberg R. BMP7 antagonizes TGF-beta-dependent fibrogenesis in mesangial cells. Am J Physiol Renal Physiol 2003;284:F1006–F1013.PubMedGoogle Scholar
  74. 74.
    Wang S, Hirschberg R. Bone morphogenetic protein-7 signals opposing transforming growth factor beta in mesangial cells. J Biol Chem 2004;279:23,200–23,206.PubMedCrossRefGoogle Scholar
  75. 75.
    Zeisberg M, Hanai J, Sugimoto H, et al. BMP-7 counteracts TGF-beta1-induced epithelial-tomesenchymal transition and reverses chronic renal injury. Nat Med 2003;9:964–968.PubMedCrossRefGoogle Scholar
  76. 76.
    Wang S, Chen Q, Simon TC, et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 2003;63:2037–2049.PubMedCrossRefGoogle Scholar
  77. 77.
    Ziyadeh FN, Hoffman BB, Han DC, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice (see comments). Proc Natl Acad Sci USA 2000;97:8015–8020.PubMedCrossRefGoogle Scholar
  78. 78.
    Callahan JF, Burgess JL, Fornwald JA, et al. Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5). J Med Chem 2002;45:999–1001.PubMedCrossRefGoogle Scholar
  79. 79.
    DaCosta Byfield S, Major C, Laping NJ, Roberts AB. SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2004;65:744–752.PubMedCrossRefGoogle Scholar
  80. 80.
    Hjelmeland MD, Hjelmeland AB, Sathornsumetee S, et al. SB-431542, a small molecule transforming growth factor-beta-receptor antagonist inhibits human glioma cell line proliferation and motility. Mol Cancer Ther 2004;3:737–745.PubMedGoogle Scholar
  81. 81.
    Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002;62:65–74.PubMedCrossRefGoogle Scholar
  82. 82.
    Laping NJ. ALK5 inhibition in renal disease. Curr Opin Pharmacol 2003;3:204–208.PubMedCrossRefGoogle Scholar
  83. 83.
    Letterio JJ, Bottinger EP. TGF-beta knockout and dominant-negative receptor transgenic mice. Miner Electrolyte Metab 1998;24:161–167.PubMedCrossRefGoogle Scholar
  84. 84.
    Yokoi H, Mukoyama M, Nagae T, et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 2004;15:1430–1440.PubMedCrossRefGoogle Scholar
  85. 85.
  86. 86.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2006

Authors and Affiliations

  • Raimund Hirschberg
    • 1
  1. 1.Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterTorrance

Personalised recommendations