Skip to main content

Advertisement

SpringerLink
Log in

The PDGF family in renal fibrosis

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

The platelet-derived growth factor (PDGF) family plays an important role in embryonic development, malignancy, wound healing, atherosclerosis, and fibrosis in multiple organs. It belongs to the best-characterized growth factor systems in normal and diseased kidneys, and there is accumulating evidence that members of the PDGF family are key players in the development of renal fibrosis independent of the underlying kidney disease. All components of the PDGF system, consisting of four isoforms (PDGF-A, -B, -C, -D) and two receptor chains (PDGFR-α and –β), are constitutively or inducibly expressed in most renal cells. They regulate multiple pathophysiologic events, ranging from cell proliferation and migration, extracellular matrix accumulation and production of pro- and anti-inflammatory mediators, to tissue permeability and hemodynamics. This review focuses on advances in defining the roles of different PDGF isoforms in the development of glomerulosclerosis and tubulointerstitial fibrosis. The recent identification of endogenous PDGF inhibitors offers additional novel therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Floege J, Johnson RJ (1995) Multiple roles for platelet-derived growth factor in renal disease. Miner Electrolyte Metab 21:271–282

    PubMed  CAS  Google Scholar 

  2. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316

    PubMed  CAS  Google Scholar 

  3. Floege J, Eitner F, Alpers CE (2008) A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 19:12–23

    Article  PubMed  CAS  Google Scholar 

  4. Floege J, Eitner F, Van Roeyen C, Ostendorf T (2003) PDGF-D and renal disease: yet another one of those growth factors? J Am Soc Nephrol 14:2690–2691

    Article  PubMed  Google Scholar 

  5. Reigstad LJ, Varhaug JE, Lillehaug JR (2005) Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family. FEBS J 272:5723–5741

    Article  PubMed  CAS  Google Scholar 

  6. Ustach CV, Huang W, Conley-Lacomb MK, Lin CY, Che M, Abrams J, Kim HR (2010) A Novel Signaling Axis of Matriptase/PDGF-D/{beta}-PDGFR in Human Prostate Cancer. Cancer Res 70:9631–9640

    Article  PubMed  CAS  Google Scholar 

  7. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312

    Article  PubMed  CAS  Google Scholar 

  8. Bonner JC (2004) Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev 15:255–273

    Article  PubMed  CAS  Google Scholar 

  9. Boor P, Konieczny A, Villa L, Kunter U, van Roeyen CR, LaRochelle WJ, Smithson G, Arrol S, Ostendorf T, Floege J (2007) PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrol Dial Transplant 22:1323–1331

    Article  PubMed  CAS  Google Scholar 

  10. Kong D, Li Y, Wang Z, Banerjee S, Ahmad A, Kim HR, Sarkar FH (2009) miR-200 regulates PDGF-D-mediated epithelial-mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells 27:1712–1721

    Article  PubMed  CAS  Google Scholar 

  11. Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS (2010) Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176:85–97

    Article  PubMed  CAS  Google Scholar 

  12. Lin SL, Kisseleva T, Brenner DA, Duffield JS (2008) Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173:1617–1627

    Article  PubMed  CAS  Google Scholar 

  13. Zeisberg M, Duffield JS (2010) Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21:1247–1253

    Article  PubMed  Google Scholar 

  14. Tallquist M, Kazlauskas A (2004) PDGF signaling in cells and mice. Cytokine Growth Factor Rev 15:205–213

    Article  PubMed  CAS  Google Scholar 

  15. Kobayashi T, Furukawa Y, Kikuchi J, Ito C, Miyata Y, Muto S, Tanaka A, Kusano E (2009) Transactivation of RON receptor tyrosine kinase by interaction with PDGF receptor beta during steady-state growth of human mesangial cells. Kidney Int 75:1173–1183

    Article  PubMed  CAS  Google Scholar 

  16. Chi SS, Vetiska SM, Gill RS, Hsiung MS, Liu F, Van Tol HH (2010) Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization. Mol Brain 3:22

    Article  PubMed  Google Scholar 

  17. Lei H, Kazlauskas A (2009) Growth factors outside of the platelet-derived growth factor (PDGF) family employ reactive oxygen species/Src family kinases to activate PDGF receptor alpha and thereby promote proliferation and survival of cells. J Biol Chem 284:6329–6336

    Article  PubMed  CAS  Google Scholar 

  18. Schneider L, Clement CA, Teilmann SC, Pazour GJ, Hoffmann EK, Satir P, Christensen ST (2005) PDGFRalphaalpha signaling is regulated through the primary cilium in fibroblasts. Curr Biol 15:1861–1866

    Article  PubMed  CAS  Google Scholar 

  19. Mendelson K, Swendeman S, Saftig P, Blobel CP (2010) Stimulation of platelet-derived growth factor receptor beta (PDGFRbeta) activates ADAM17 and promotes metalloproteinase-dependent cross-talk between the PDGFRbeta and epidermal growth factor receptor (EGFR) signaling pathways. J Biol Chem 285:25024–25032

    Article  PubMed  CAS  Google Scholar 

  20. Shimizu H, Nakagawa Y, Murakami C, Aoki N, Kim-Mitsuyama S, Miyazaki H (2010) Protein tyrosine phosphatase PTPepsilonM negatively regulates PDGF beta-receptor signaling induced by high glucose and PDGF in vascular smooth muscle cells. Am J Physiol Cell Physiol 299:C1144–1152

    Article  PubMed  CAS  Google Scholar 

  21. Venkatesan B, Ghosh-Choudhury N, Das F, Mahimainathan L, Kamat A, Kasinath BS, Abboud HE, Choudhury GG (2008) Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B. FASEB J 22:3469–3482

    Article  PubMed  CAS  Google Scholar 

  22. Betsholtz C, Lindblom P, Bjarnegard M, Enge M, Gerhardt H, Lindahl P (2004) Role of platelet-derived growth factor in mesangium development and vasculopathies: lessons from platelet-derived growth factor and platelet-derived growth factor receptor mutations in mice. Curr Opin Nephrol Hypertens 13:45–52

    Article  PubMed  CAS  Google Scholar 

  23. Eitner F, Bucher E, van Roeyen C, Kunter U, Rong S, Seikrit C, Villa L, Boor P, Fredriksson L, Backstrom G, Eriksson U, Ostman A, Floege J, Ostendorf T (2008) PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J Am Soc Nephrol 19:281–289

    Article  PubMed  CAS  Google Scholar 

  24. Ding H, Wu X, Bostrom H, Kim I, Wong N, Tsoi B, O'Rourke M, Koh GY, Soriano P, Betsholtz C, Hart TC, Marazita ML, Field LL, Tam PP, Nagy A (2004) A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 36:1111–1116

    Article  PubMed  CAS  Google Scholar 

  25. Soriano P (1994) Abnormal kidney development and hematological disorders in PDGF beta- receptor mutant mice. Genes Dev 8:1888–1896

    Article  PubMed  CAS  Google Scholar 

  26. Sano H, Ueda Y, Takakura N, Takemura G, Doi T, Kataoka H, Murayama T, Xu Y, Sudo T, Nishikawa S, Fujiwara H, Kita T, Yokode M (2002) Blockade of platelet-derived growth factor receptor-beta pathway induces apoptosis of vascular endothelial cells and disrupts glomerular capillary formation in neonatal mice. Am J Pathol 161:135–143

    Article  PubMed  CAS  Google Scholar 

  27. Bjarnegard M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fassler R, Betsholtz C (2004) Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development 131:1847–1857

    Article  PubMed  CAS  Google Scholar 

  28. Eitner F, Ostendorf T, Van Roeyen C, Kitahara M, Li X, Aase K, Grone HJ, Eriksson U, Floege J (2002) Expression of a novel PDGF isoform, PDGF-C, in normal and diseased rat kidney. J Am Soc Nephrol 13:910–917

    PubMed  CAS  Google Scholar 

  29. Eitner F, Ostendorf T, Kretzler M, Cohen CD, Eriksson U, Grone HJ, Floege J (2003) PDGF-C expression in the developing and normal adult human kidney and in glomerular diseases. J Am Soc Nephrol 14:1145–1153

    Article  PubMed  CAS  Google Scholar 

  30. Changsirikulchai S, Hudkins KL, Goodpaster TA, Volpone J, Topouzis S, Gilbertson DG, Alpers CE (2002) Platelet-derived growth factor-D expression in developing and mature human kidneys. Kidney Int 62:2043–2054

    Article  PubMed  CAS  Google Scholar 

  31. Ostendorf T, Van Roeyen CR, Peterson JD, Kunter U, Eitner F, Hamad AJ, Chan G, Jia XC, Macaluso J, Gazit-Bornstein G, Keyt BA, Lichenstein HS, LaRochelle WJ, Floege J (2003) A Fully Human Monoclonal Antibody (CR002) Identifies PDGF-D as a Novel Mediator of Mesangioproliferative Glomerulonephritis. J Am Soc Nephrol 14:2237–2247

    Article  PubMed  CAS  Google Scholar 

  32. Taneda S, Hudkins KL, Topouzis S, Gilbertson DG, Ophascharoensuk V, Truong L, Johnson RJ, Alpers CE (2003) Obstructive Uropathy in Mice and Humans: Potential Role for PDGF-D in the Progression of Tubulointerstitial Injury. J Am Soc Nephrol 14:2544–2555

    Article  PubMed  CAS  Google Scholar 

  33. Iida H, Seifert R, Alpers CE, Gronwald RG, Phillips PE, Pritzl P, Gordon K, Gown AM, Ross R, Bowen-Pope DF, Johnson R (1991) Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat. Proc Natl Acad Sci USA 88:6560–6564

    Article  PubMed  CAS  Google Scholar 

  34. Alpers CE, Davis CL, Barr D, Marsh CL, Hudkins KL (1996) Identification of platelet-derived growth factor A and B chains in human renal vascular rejection. Am J Pathol 148:439–451

    PubMed  CAS  Google Scholar 

  35. Floege J, Hudkins KL, Davis CL, Schwartz SM, Alpers CE (1998) Expression of PDGF alpha-receptor in renal arteriosclerosis and rejecting renal transplants. J Am Soc Nephrol 9:211–223

    PubMed  CAS  Google Scholar 

  36. Triantafyllopoulou A, Franzke CW, Seshan SV, Perino G, Kalliolias GD, Ramanujam M, van Rooijen N, Davidson A, Ivashkiv LB (2010) Proliferative lesions and metalloproteinase activity in murine lupus nephritis mediated by type I interferons and macrophages. Proc Natl Acad Sci USA 107:3012–3017

    Article  PubMed  CAS  Google Scholar 

  37. Hotchkiss H, Chu TT, Hancock WW, Schroppel B, Kretzler M, Schmid H, Liu Y, Dikman S, Akalin E (2006) Differential expression of profibrotic and growth factors in chronic allograft nephropathy. Transplantation 81:342–349

    Article  PubMed  CAS  Google Scholar 

  38. Liu G, Changsirikulchai S, Hudkins KL, Banas MC, Kowalewska J, Yang X, Wietecha TA, Volpone J, Gilbertson DG, Alpers CE (2008) Identification of platelet-derived growth factor D in human chronic allograft nephropathy. Hum Pathol 39:393–402

    Article  PubMed  CAS  Google Scholar 

  39. Boor P, Eitner F, Cohen CD, Lindenmeyer MT, Mertens PR, Ostendorf T, Floege J (2009) Patients with IgA nephropathy exhibit high systemic PDGF-DD levels. Nephrol Dial Transplant 24:2755–2762

    Article  PubMed  Google Scholar 

  40. Floege J, Eng E, Young BA, Alpers CE, Barrett TB, Bowen-Pope DF, Johnson RJ (1993) Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin Invest 92:2952–2962

    Article  PubMed  CAS  Google Scholar 

  41. Riley SG, Steadman R, Williams JD, Floege J, Phillips AO (1999) Augmentation of kidney injury by basic fibroblast growth factor or platelet-derived growth factor does not induce progressive diabetic nephropathy in the Goto Kakizaki model of non-insulin-dependent diabetes. J Lab Clin Med 134:304–312

    Article  PubMed  CAS  Google Scholar 

  42. Isaka Y, Fujiwara Y, Ueda N, Kaneda Y, Kamada T, Imai E (1993) Glomerulosclerosis induced by in vivo transfection of transforming growth factor-beta or platelet-derived growth factor gene into the rat kidney. J Clin Invest 92:2597–2601

    Article  PubMed  CAS  Google Scholar 

  43. Hudkins KL, Gilbertson DG, Carling M, Taneda S, Hughes SD, Holdren MS, Palmer TE, Topouzis S, Haran AC, Feldhaus AL, Alpers CE (2004) Exogenous PDGF-D is a potent mesangial cell mitogen and causes a severe mesangial proliferative glomerulopathy. J Am Soc Nephrol 15:286–298

    Article  PubMed  CAS  Google Scholar 

  44. Suzuki A, Iwatani H, Ito T, Imai E, Okabe M, Nakamura H, Isaka Y, Yamato M, Hori M (2004) Platelet-derived growth factor plays a critical role to convert bone marrow cells into glomerular mesangial-like cells. Kidney Int 65:15–24

    Article  PubMed  CAS  Google Scholar 

  45. Tang WW, Ulich TR, Lacey DL, Hill DC, Qi M, Kaufman SA, Van GY, Tarpley JE, Yee JS (1996) Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am J Pathol 148:1169–1180

    PubMed  CAS  Google Scholar 

  46. van Roeyen CR, Eitner F, Boor P, Moeller MJ, Bücher E, Villa L, Banas M, Hudkins KL, Alpers CE, Ostendorf T, Floege J (2005) Induction of progressive glomerulonephritis via podocyte specfic overexpression of platelet derived growth factor (PDGF)-D [Abstract]. J Am Soc Nephrol 16:2717

    Google Scholar 

  47. Ostendorf T, Kunter U, Grone HJ, Bahlmann F, Kawachi H, Shimizu F, Koch KM, Janjic N, Floege J (2001) Specific antagonism of PDGF prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 12:909–918

    PubMed  CAS  Google Scholar 

  48. Ostendorf T, Rong S, Boor P, Wiedemann S, Kunter U, Haubold U, van Roeyen CR, Eitner F, Kawachi H, Starling G, Alvarez E, Smithson G, Floege J (2006) Antagonism of PDGF-D by human antibody CR002 prevents renal scarring in experimental glomerulonephritis. J Am Soc Nephrol 17:1054–1062

    Article  PubMed  CAS  Google Scholar 

  49. Hawthorne T, Giot L, Blake L, Kuang B, Gerwien R, Smithson G, Hahne W, Mansfield T, Starling GC, Pochart P, Hoelscher D, Halvorsen YD (2008) A phase I study of CR002, a fully-human monoclonal antibody against platelet-derived growth factor-D. Int J Clin Pharmacol Ther 46:236–244

    PubMed  CAS  Google Scholar 

  50. Ostendorf T, Kunter U, van Roeyen C, Dooley S, Janjic N, Ruckman J, Eitner F, Floege J (2002) The effects of platelet-derived growth factor antagonism in experimental glomerulonephritis are independent of the transforming growth factor-beta system. J Am Soc Nephrol 13:658–667

    PubMed  CAS  Google Scholar 

  51. Shinkai Y, Cameron JS (1987) Trial of platelet-derived growth factor antagonist, trapidil, in accelerated nephrotoxic nephritis in the rabbit. Br J Exp Pathol 68:847–852

    PubMed  CAS  Google Scholar 

  52. Nakagawa T, Sasahara M, Haneda M, Kataoka H, Nakagawa H, Yagi M, Kikkawa R, Hazama F (1999) Role of PDGF B-chain and PDGF receptors in rat tubular regeneration after acute injury. Am J Pathol 155:1689–1699

    Article  PubMed  CAS  Google Scholar 

  53. Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, Walters B, Shevtsov S, Pesant S, Clubb FJ, Rosenzweig A, Salomon RN, Van Etten RA, Alroy J, Durand JB, Force T (2006) Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 12:908–916

    Article  PubMed  Google Scholar 

  54. Jhaveri KD, Flombaum CD, Kroog G, Glezerman IG (2010) Nephrotoxicities Associated with the Use of Tyrosine Kinase Inhibitors: A Single-Center Experience and Review of the Literature. Nephron Clin Pract 117:c312–c319

    Article  PubMed  Google Scholar 

  55. Ludewig D, Kosmehl H, Sommer M, Bohmer FD, Stein G (2000) PDGF receptor kinase blocker AG1295 attenuates interstitial fibrosis in rat kidney after unilateral obstruction. Cell Tissue Res 299:97–103

    Article  PubMed  CAS  Google Scholar 

  56. Leveen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C (1994) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8:1875–1887

    Article  PubMed  CAS  Google Scholar 

  57. Nakagawa T, Izumino K, Ishii Y, Oya T, Hamashima T, Jie S, Ishizawa S, Tomoda F, Fujimori T, Nabeshima YI, Inoue H, Sasahara M (2011) Roles of PDGF receptor-beta in the structure and function of postnatal kidney glomerulus. Nephrol Dial Transplant 26:458–468

    Article  PubMed  CAS  Google Scholar 

  58. Kishioka H, Fukuda N, Wen-Yang H, Nakayama M, Watanabe Y, Kanmatsuse K (2001) Effects of PDGF A-chain antisense oligodeoxynucleotides on growth of cardiovascular organs in stroke-prone spontaneously hypertensive rats. Am J Hypertens 14:439–445

    Article  PubMed  CAS  Google Scholar 

  59. Boor P, van Roeyen CR, Kunter U, Villa L, Bucher E, Hohenstein B, Hugo CP, Eriksson U, Satchell SC, Mathieson PW, Eitner F, Floege J, Ostendorf T (2010) PDGF-C mediates glomerular capillary repair. Am J Pathol 177:58–69

    Article  PubMed  CAS  Google Scholar 

  60. van Roeyen CR, Eitner F, Scholl T, Boor P, Kunter U, Planque N, Grone HJ, Bleau AM, Perbal B, Ostendorf T, Floege J (2008) CCN3 is a novel endogenous PDGF-regulated inhibitor of glomerular cell proliferation. Kidney Int 73:86–94

    Article  PubMed  Google Scholar 

  61. Barnes JL, Woodruff KA, Levine SP, Abboud HE (1996) Inhibition of mesangial cell proliferation by platelet factor 4. J Am Soc Nephrol 7:991–998

    PubMed  CAS  Google Scholar 

  62. Ishizawa K, Dorjsuren N, Izawa-Ishizawa Y, Sugimoto R, Ikeda Y, Kihira Y, Kawazoe K, Tomita S, Tsuchiya K, Minakuchi K, Tamaki T (2009) Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration. J Endocrinol 202:309–316

    Article  PubMed  CAS  Google Scholar 

  63. Abrass CK, Hansen KM, Patton BL (2010) Laminin alpha4-null mutant mice develop chronic kidney disease with persistent overexpression of platelet-derived growth factor. Am J Pathol 176:839–849

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We apologize to all authors whose important work we could not cite due to space limitations. For more detailed aspects of PDGF biology, the reader is referred to original studies and other reviews, some of which are cited here. This study was supported by grants from the Deutsche Forschungsgemeinschaft [SFB/TRR 57, projects P14 (FE, TO) , P17 and P19 (JF); SFB542, project C7 (TO, JF)].

Author information

Authors and Affiliations

  1. Department of Nephrology, RWTH University of Aachen, Pauwelsstr. 30, 52074, Aachen, Germany

    Tammo Ostendorf, Frank Eitner & Jürgen Floege

Authors
  1. Tammo Ostendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank Eitner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jürgen Floege
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tammo Ostendorf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ostendorf, T., Eitner, F. & Floege, J. The PDGF family in renal fibrosis. Pediatr Nephrol 27, 1041–1050 (2012). https://doi.org/10.1007/s00467-011-1892-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-011-1892-z

Keywords

Search

Navigation