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Therapeutic Potential of Anti-Midkine Therapy in Progressive Renal Diseases

Research Project

Project/Area Number 15590849
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionNagoya University

Principal Investigator

YUZAWA Yukio  Nagoya University, Graduate School of Medicine, Assistant professor, 大学院・医学系研究科, 講師 (00191479)

Co-Investigator(Kenkyū-buntansha) MATSUO Seiichi  Nagoya University, Graduate School of Medicine, professor, 大学院・医学系研究科, 教授 (70190410)
KADOMATSU Kenji  Nagoya University, Graduate School of Medicine, professor, 大学院・医学系研究科, 教授 (80204519)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
KeywordsMidkine / anti-sense ODN / apoptosis / Cisplatin / tubulointerstitial injury / DM / glomerulosclerosis / ERK / I型糖尿病
Research Abstract

The following experiments have been performed in order to clarify the potential of midkine(MK) as a candidate of molecular target for the prevention of progressive renal diseases.
(1)The inhibitory effects of MK antisense oligodeoxinucleotide(ODN) "in vivo" in sevelal animal models of renal injuries, such as ischemic renal reperfusion injury, cysplatin nephropathy and STZ induced DM model.
(2)The signal pathway of MK-dependent expression of MCP-1 and MIP-2 in cultured mesangial cells and renal tubular epithelial cells.
(3)The profile of the genes which are up-regulated or down-regulated after stimulation with MK by DNA tip analysis.
RESULTS
(1)Intravenous injection of MK antisense-ODN preferentially incorporated in the proximal tubules in the kidney, and significantly inhibited the expression of MK in the proximal tubules. Furthermore, MK antisense-ODN successfully inhibited the process of progressive renal injuries in ischemic renal reperfusion injury, and cysplatin nephropathy.
(2)In STZ induced DM model, expression of MK in glomeruli was increased The level of glomerular sclerosis which was prominent in wild type mice was much less in MK knockout mice, showing that MK involves in the process of diabetic nephrosclerosis. Further studies showed that MK contributes to the glomerular sclerosis by activation of PKCb and ARK, and by enhancement of macrophage influx in glomeruli.
(3)The urinary excretion of MK in DM patients was well correlated with the pathological stage of DM nephropathy.
These results strongly suggest the prominent potential of MK as a candidate of molecular target for the prevention of progressive renal diseases. The signal pathway through MK and its receptors (LRP and Megalin) would be important for the clinical application of anti-MK therapy.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (18 results)

All 2005 2004 Other

All Journal Article (16 results) Publications (2 results)

  • [Journal Article] Midkine Antisense Oligodeoxyribonucleotide Inhibits Renal Damage Induced by Ischemic Reperfusion2005

    • Author(s)
      Sato W et al.
    • Journal Title

      Kidney International (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Geranylgeranylacetone Ameliorates Ischemic Acute Renal Failure via Induction of Hsp702005

    • Author(s)
      Suzuki S et al.
    • Journal Title

      Kidney International (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Midkine Antisense Oligodeoxyribonucleotide Inhibits Renal Damage Induced by Ischemic Reperfusion2005

    • Author(s)
      Waichi Sato, Kenji Kadomatsu, Yukio Yuzawa, Yshifumi Takei, Hanyo Kawai, Tomoki Kosugi, Syouichi Maruyama, Yoshiki Morita, Takashi Muramatsu, Seiichi Matsuo
    • Journal Title

      Kidney International (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Geranylgeranylacetone Ameliorates Ischemic Acute Renal Failure via Induction of Hsp70.2005

    • Author(s)
      Satoshi Suzuki, Shoichi Maruyama, Waichi Sato, Yoshiki Morita, Fumihiko Sato, Yusuke Miki, Sawako Kato, Masahisa Katsuno, Gen Sobue, Yukio Yuzawa, Seiichi Matsuo
    • Journal Title

      Kidney International (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Geranylgeranylacetone Ameliorates Ischemic Acute Renal Failure via Induction of Hsp702005

    • Author(s)
      Suzuki S, et al.
    • Journal Title

      Kidney International (In press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics.2005

    • Author(s)
      Takei Y, et al.
    • Journal Title

      Cancer Research 64

      Pages: 3365-3370

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics.2004

    • Author(s)
      Takei Y et al.
    • Journal Title

      Cancer Research 64

      Pages: 3365-3370

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Endotoxin induced Chemokine Expression in Murine Peritoneal Mesothelial Cells.2004

    • Author(s)
      Kato S et al.
    • Journal Title

      Journal of American Society of Nephrology 15

      Pages: 1289-1299

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Midkine expression in rat spinal motor neurons following sciatic nerve injury2004

    • Author(s)
      Sakakima H et al.
    • Journal Title

      Developmental Brain Research 153

      Pages: 251-260

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lack of the growth factor Midkine enhances survival against cisplatin-induced renal damage2004

    • Author(s)
      Kawai H et al.
    • Journal Title

      American Journal of Pathology 165

      Pages: 1603-1612

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A small interfering RNA targeting vascular endothelial growth factor as cancer therapeutics2004

    • Author(s)
      Takei Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T.
    • Journal Title

      Cancer Res 64

      Pages: 3365-3370

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Endotoxin induced Chemokine Expression in Murine Peritoneal Mesothelial Cells.2004

    • Author(s)
      Sawako Kato, Yukio Yuzawa, Naotake Tsuboi, Shoichi Maruyama, Yoshiki Morita, Tetsuya Matsuguchi, Seiichi Matsuo
    • Journal Title

      J Am Soc Nephrol 15

      Pages: 1289-1299

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Midkine expression in rat spinal motor neurons following sciatic nerve injury.2004

    • Author(s)
      Sakakima H, Yoshida Y, Kadomatsu K, Yuzawa Y, Matsuo S, Muramatsu T
    • Journal Title

      Dev Brain Res 153

      Pages: 251-260

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Lack of the growth factor Midkine enhances survival against cisplatin-induced renal damage.2004

    • Author(s)
      Kawai H, Sato W, Yuzawa Y, Kosugi T, Matsuo S, Takei Y, Kadomatsu K, Muramatsu T
    • Journal Title

      Am J Pathol 165

      Pages: 1603-1612

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Midkine expression in rat spinal motor neurons following sciatic nerve injury2004

    • Author(s)
      Sakakima H, et al.
    • Journal Title

      Developmental Brain Research 153

      Pages: 251-260

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Lack of the growth factor Midkine enhances survival against cisplatin-induced renal damage2004

    • Author(s)
      Kawai H, et al.
    • Journal Title

      American Journal of Pathology 165

      Pages: 1603-1612

    • Related Report
      2004 Annual Research Report
  • [Publications] Shimizu H: "Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria"Journal of American Society of Nephrology. 14. 1496-1505 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Liu M: "The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids"Clinical and Experimental Nephrology. 7. 187-191 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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