Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice

Gene Therapy volume 8, pages 1470–1479 (2001)Cite this article

Abstract

The progression of chronic renal diseases is considered as an irreversible process that eventually leads to end-stage renal failure characterized by extensive tissue fibrosis. At present, chronic renal fibrosis is incurable and the incidence of affected patients is on the rise worldwide. In this study, we demonstrate that delivery of hepatocyte growth factor (HGF) gene via systemic administration of naked plasmid vector markedly ameliorated renal fibrosis in an animal model of chronic renal disease induced by unilateral ureteral obstruction. A high level of exogenous HGF protein was detected in the obstructed kidneys following intravenous injection of naked plasmid encoding human HGF. Delivery of human HGF gene induced a sustained activation of extracellular signal-regulated kinases-1 and -2 in the obstructed kidneys. Exogenous HGF expression dramatically inhibited α-smooth muscle actin expression, attenuated renal interstitial accumulation and deposition of collagen I and fibronectin. In addition, exogenous HGF suppressed renal expression of pro-fibrogenic cytokine TGF-β1 and its type I receptor in vivo. These results suggest that systemic administration of naked plasmid vector introduces a high level of exogenous HGF to the diseased kidneys, and that HGF gene transfer may provide a novel therapeutic strategy for amelioration of chronic renal fibrosis in vivo. Gene Therapy (2001) 8, 1470–1479.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Eddy AA . Molecular insights into renal interstitial fibrosis J Am Soc Nephrol 1996 7: 2495–2508

    CAS  PubMed  Google Scholar 

  2. Remuzzi G, Bertani T . Pathophysiology of progressive nephropathies N Engl J Med 1998 339: 1448–1456

    Article  CAS  PubMed  Google Scholar 

  3. Port FK, Fenton SSA, Mazzuchi N . ESRD throughout the world: morbidity, mortality and quality of life Kidney Int 2000 57: S1–S2

    Article  Google Scholar 

  4. Kawaida K, Matsumoto K, Shimazu H, Nakamura T . Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice Proc Natl Acad Sci USA 1994 91: 4357–4361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Miller SB, Martin DR, Kissane J, Hammerman MR . Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats Am J Physiol 1994 266: F129–F134

    PubMed  Google Scholar 

  6. Hammerman MR et al. Acute renal failure. III. The role of growth factors in the process of renal regeneration and repair Am J Physiol Renal Physiol 2000 279: F3–F11

    Article  Google Scholar 

  7. Vargas GA, Hoeflich A, Jehle PM . Hepatocyte growth factor in renal failure: promise and reality Kidney Int 2000 57: 1426–1436

    Article  CAS  PubMed  Google Scholar 

  8. Zarnegar R, Michalopoulos GK . The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis J Cell Biol 1995 129: 1177–1180

    Article  CAS  PubMed  Google Scholar 

  9. Matsumoto K, Nakamura T . Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases Kidney Int 2001 59: 2023–2038

    Article  CAS  PubMed  Google Scholar 

  10. Michalopoulos GK, DeFrances MC . Liver regeneration Science 1997 276: 60–66

    Article  CAS  PubMed  Google Scholar 

  11. Liu Y, Sun AM, Dworkin LD . Hepatocyte growth factor protects renal epithelial cells from apoptotic cell death Biochem Biophys Res Commun 1998 246: 821–826

    Article  CAS  PubMed  Google Scholar 

  12. Yo Y et al. Potential role of hepatocyte growth factor in the maintenance of renal structure: anti-apoptotic action of HGF on epithelial cells Kidney Int 1998 54: 1128–1138

    Article  CAS  PubMed  Google Scholar 

  13. Liu Y . Hepatocyte growth factor promotes renal epithelial cell survival by dual mechanisms Am J Physiol Renal Physiol 1999 277: F624–F633

    Article  CAS  Google Scholar 

  14. Fornoni A et al. Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis Am J Pathol 2001 158: 275–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mizuno S et al. Hepatocyte growth factor prevents renal fibrosis and dysfunction in a mouse model of chronic renal disease J Clin Invest 1998 101: 1827–1834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ueki T et al. Hepatocyte growth factor gene therapy of liver cirrhosis in rats Nat Med 1999 5: 226–230

    Article  CAS  PubMed  Google Scholar 

  17. Liu Y, Rajur K, Tolbert E, Dworkin LD . Endogenous hepatocyte growth factor ameliorates chronic renal injury by activating matrix degradation pathways Kidney Int 2000 58: 2028–2043

    Article  CAS  PubMed  Google Scholar 

  18. Mizuno S et al. Reciprocal balance of hepatocyte growth factor and transforming growth factor-b1 in renal fibrosis in mice Kidney Int 2000 57: 937–948

    Article  CAS  PubMed  Google Scholar 

  19. Liu ML, Mars WM, Zarnegar R, Michalopoulos GK . Uptake and distribution of hepatocyte growth factor in normal and regenerating adult rat liver Am J Pathol 1994 144: 129–140

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang J et al. Sustained expression of naked plasmid DNA encoding hepatocyte growth factor in mice promotes liver and overall body growth Hepatology 2001 33: 848–859

    Article  CAS  PubMed  Google Scholar 

  21. Pearson G et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions Endocr Rev 2001 22: 153–183

    CAS  PubMed  Google Scholar 

  22. Chang L, Karin M . Mammalian MAP kinase signaling cascades Nature 2001 410: 37–40

    Article  CAS  PubMed  Google Scholar 

  23. Matsumoto K, Mizuno S, Nakamura T . Hepatocyte growth factor in renal regeneration, renal disease and potential therapeutics Curr Opin Nephrol Hypertens 2000 9: 395–402

    Article  CAS  PubMed  Google Scholar 

  24. Takayama H et al. Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor Lab Invest 1997 77: 131- 138

    Google Scholar 

  25. Kelley VR, Suhatme VP . Gene transfer in the kidney Am J Physiol 1999 276: F1–F9

    CAS  PubMed  Google Scholar 

  26. Imai E, Isaka Y . New paradigm of gene therapy: skeletal-muscle-targeting gene therapy for kidney disease Nephron 1999 83: 296–300

    Article  CAS  PubMed  Google Scholar 

  27. Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA Gene Therapy 1999 6: 1258–1266

    Article  CAS  PubMed  Google Scholar 

  28. Li S, Huang L . Nonviral gene therapy: promises and challenges Gene Therapy 2000 7: 31–34

    Article  CAS  PubMed  Google Scholar 

  29. He Y et al. Intravenous injection of naked DNA encoding secreted flt3 ligand dramatically increases the number of dendritic cells and natural killer cells in vivo Hum Gene Ther 2000 11: 547–554

    Article  CAS  PubMed  Google Scholar 

  30. Liu Y et al. Up-regulation of hepatocyte growth factor receptor: an amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure Kidney Int 1999 55: 442–453

    Article  CAS  PubMed  Google Scholar 

  31. Lai LW, Moeckel GW, Lien YHH . Kidney-targeted liposome-mediated gene transfer in mice Gene Therapy 1997 4: 426–431

    Article  CAS  PubMed  Google Scholar 

  32. Shiota G, Wang TC, Nakamura T, Schmidt EV . Hepatocyte growth factor in transgenic mice: effects on hepatocyte growth, liver regeneration and gene expression Hepatology 1994 19: 962–972

    Article  CAS  PubMed  Google Scholar 

  33. Bell A et al. The five amino acid-deleted isoform of hepatocyte growth factor promotes carcinogenesis in transgenic mice Oncogene 1999 18: 887–895

    Article  CAS  PubMed  Google Scholar 

  34. Garcia-Ocana A et al. Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia J Biol Chem 2000 275: 1226–1232

    Article  CAS  PubMed  Google Scholar 

  35. Roberts IS et al. Interstitial myofibroblasts: predictors of progression in membranous nephropathy J Clin Pathol 1997 50: 123–127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ng YY et al. Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats Kidney Int 1998 54: 864–876

    Article  CAS  PubMed  Google Scholar 

  37. Okada H, Danoff TM, Kalluri R, Neilson EG . Early role of Fsp1 in epithelial-mesenchymal transformation Am J Physiol 1997 273: F563–F574

    Article  CAS  PubMed  Google Scholar 

  38. Sharma K, Ziyadeh FN . The emerging role of transforming growth factor-β in kidney diseases Am J Physiol 1994 266: F829–F842

    CAS  PubMed  Google Scholar 

  39. Border WA, Noble NA . Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis Hypertension 1998 31: 181–188

    Article  CAS  PubMed  Google Scholar 

  40. Massague J, Blain SW, Lo RS . TGF-beta signaling in growth control, cancer and heritable disorders Cell 2000 103: 295–309

    Article  CAS  PubMed  Google Scholar 

  41. Schiffer M et al. Smad proteins and transforming growth factor-beta signaling Kidney Int 2000 58: S45–S52

    Article  Google Scholar 

  42. Isaka Y et al. Transforming growth factor-beta1 antisense oligodeoxynucleotides block interstitial fibrosis in unilateral ureteral obstruction Kidney Int 2000 58: 1885–1892

    Article  CAS  PubMed  Google Scholar 

  43. Kretzschmar M, Doody J, Timokhina I, Massague J . A mechanism of repression of TGFβ/Smad signaling by oncogenic Ras Genes Dev 1999 13: 804–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chevalier RL et al. Renal tubulointerstitial injury from ureteral obstruction in the neonatal rat is attenuated by IGF-1 Kidney Int 2000 57: 882–890

    Article  CAS  PubMed  Google Scholar 

  45. Liu Y et al. Constitutive expression of HGF modulates renal epithelial cell phenotype and induces c-met and fibronectin expression Exp Cell Res 1998 242: 174–185

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health grants DK-02611, and DK-54922 (YL). JY was supported in part by the Pathology Postdoctoral Research Training Grant from the Department of Pathology at the University of Pittsburgh School of Medicine.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    J Yang, C Dai & Y Liu

Authors
  1. J Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, J., Dai, C. & Liu, Y. Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice. Gene Ther 8, 1470–1479 (2001). https://doi.org/10.1038/sj.gt.3301545

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301545

Keywords

This article is cited by

Search

Advanced search

Quick links