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Pathogenesis and treatment of diabetic nephropathy

Research Project

Project/Area Number 16590786
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

ARAI Hidenori  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 講師 (60232021)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsdiabetic nephropathy / Akt / mTOR / Gas6 / mesangial cell / 肥大 / ラパマイシン
Research Abstract

Background. We have already reported that Gas6 is involved in glomerular hypertrophy observed in diabetic nephropathy. However, the molecular mechanisms involved in glomerular hypertrophy are still unknown, especially in vivo.
Methods. In vivo, diabetes was induced in rats and mice by streptozotocin (STZ) and the activation of the Akt/mTOR pathway was examined in glomeruli. In vitro, mesangial hypertrophy was assessed by [^3H]leucine incorporation and measuring cell areas.
Results. Akt, p70 S6 kinase, and 4E-BP-1 were induced and phosphorylated in rat glomerular lysates after 12 weeks of STZ injection when mesangial and glomerular hypertrophy was observed. We then examined the role of Gas6 by treating STZ-rats with warfarin and found that warfarin treatment inhibited the phosphorylation of these molecules as well as the hypertrophy. We next examined whether high glucose stimulation can induce the expression of Gas6/Axl in mesangial cells. Stimulation of the cells with 25 mmol/l of glucose increased the expression of Gas6/Axl and mesangial cell size compared with that with 5.6 mmol/l of glucose. This hypertrophic effect was abolished in mesangial cells derived from Gas6 knockout mice. We also found that LY294002 and rapamycin blocked Gas6-induced activation of the Akt/mTOR pathway and mesangial hypertrophy. Furthermore, less phosphorylated Akt-positive or 4E-BP-1-positive areas were found in STZ-treated Gas6 knockout mice than in STZ-treated wild type mice.
Conclusions. Our study indicates that the Akt/mTOR pathway is a key signaling cascade in Gas6-mediated mesangial and glomerular hypertrophy and revealed a crucial role of Gas6/Axl and the Akt/mTOR pathway in the development of diabetic nephropathy.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (18 results)

All 2006 2005 2004 Other

All Journal Article (18 results)

  • [Journal Article] Expression of Smadlis directly associated with mesangial matrix expansion in rat diabetic nephropathy.2006

    • Author(s)
      Matsubara T, Abe H, Arai H, et al.
    • Journal Title

      Laboratory Investigation (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation.2006

    • Author(s)
      Tanaka M, Arai H, et al.
    • Journal Title

      Kidney International 67

      Pages: 2123-2133

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy.2006

    • Author(s)
      Matsubara T, Abe H, Arai H, et al.
    • Journal Title

      Laboratory Investigation (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Establishment of a diabetic mouse model with progressive diabetic nephropathy.2005

    • Author(s)
      Inada A, Nagai K, Arai H, et al.
    • Journal Title

      American Journal of Pathology 167

      Pages: 327-336

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy.2005

    • Author(s)
      Nagai K, Matsubara T, Arai H, et al.
    • Journal Title

      Kidney International 68

      Pages: 552-561

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis.2005

    • Author(s)
      Takahashi T, Abe H, Arai, H, et al.
    • Journal Title

      Journal of Biological Chemistry 280

      Pages: 7100-7106

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells.2005

    • Author(s)
      Zhuge X, Murayama T, Arai H, et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 331

      Pages: 1295-1300

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy.2005

    • Author(s)
      Nagai K, Matsubara T, Arai H et al.
    • Journal Title

      Kidney International 68

      Pages: 552-561

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis.2005

    • Author(s)
      Takahashi T, Abe H, Arai, H, Matsubara T, Nagai K, et al.
    • Journal Title

      J Biol Chem. 280

      Pages: 7100-7106

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Alterations in expression of angiopoietins and the Tie-2 receptor in the retina of streptozotocin induced diabetic rats.2004

    • Author(s)
      Ohashi H, Takagi H, Koyama S, Oh H, Watanabe D, et al.
    • Journal Title

      Mol Vis. 10

      Pages: 608-617

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.2004

    • Author(s)
      Kobayashi T, Tahara Y, Matsumoto M, Iguchi M, Sano H, et al.
    • Journal Title

      J Clin Invest 114

      Pages: 784-794

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of bone marrow-derived progenitor cells in cuff-induced vascular injury in mice.2004

    • Author(s)
      Xu, Y., Arai, H., Zhuge, X., Sano, H., Murayama, T., et al.
    • Journal Title

      Arterioscler Thromb Vasc Biol 24

      Pages: 477-482

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy.2004

    • Author(s)
      Ohashi S, Abe H, Takahashi T, Yamamoto Y, et al.
    • Journal Title

      J Biol Chem. 279

      Pages: 19816-19823

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Type IV collagen is transcriptionally regulated by Small under advanced glycation end product(AGE) stimulation.2004

    • Author(s)
      Abe H, Matsubara T, Iehara N, Nagai K, Arai H, et al.
    • Journal Title

      J Biol Chem. 279

      Pages: 14201-14206

    • Related Report
      2004 Annual Research Report
  • [Journal Article] CXCL16 is a novel angiogenic factor for human umbilical vein endothelial cells.

    • Author(s)
      Zhuge X, Murayama T, Arai H, et al.
    • Journal Title

      Biochemical and Biophysical Research Communications (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephoropathy.

    • Author(s)
      Nagai K, Matsubara T, Mima A, Sumi E, Kanamori H, et al.
    • Journal Title

      Kidney International (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation.

    • Author(s)
      Tanaka M, Arai H, Liu N, Nogaki F, Nomura K, et al.
    • Journal Title

      Kidney International in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Serum Lipid Survey and its Recent Trend in the General Japanese Population in 2000

    • Author(s)
      Arai H, Yamamoto A, Matsuzawa Y, Saito Y, et al.
    • Journal Title

      J Arteriosclerosis Thrombosis (in press)

    • NAID

      10018366076

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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