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Study of renal diseases caused by podocyte injury

Research Project

Project/Area Number 15209030
Research Category

Grant-in-Aid for Scientific Research (A)

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

Principal Investigator

MATSUSAKA Taiji  Tokai University, Institute of Medical Sciences, Associate Professor, 総合医学研究所, 助教授 (50317749)

Co-Investigator(Kenkyū-buntansha) ICHIKAWA Iekuni  Tokai University, School of Medicine, Professor, 医学部, 教授 (80317768)
NIIMURA Fumio  Tokai University, School of Medicine, Assistant Professor, 医学部, 講師 (30282750)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥49,270,000 (Direct Cost: ¥37,900,000、Indirect Cost: ¥11,370,000)
Fiscal Year 2005: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2004: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2003: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
Keywordspodocyte / glomerular sclerosis / transgenic mice / HIV-1 associated nephropathy / angiotensin / chronic renal failure / actinin / 糸球体上皮細胞 / アンジオテンシン / 糖尿病腎症
Research Abstract

To investigate causal relationship between podocyte injury and glomerular sclerosis, a hallmark of chronic renal failure, we developed a transgenic mouse line (NEP25) in which podocyte-selective injury can be induced by a single injection of immunotoxin (LMB2). After LMB2 injection, NEP25 mice manifested injury of podocytes and other glomerular cells and rapidly developed glomerular sclerosis. Labeling of the podocyte-lineage utilizing the Cre-loxP system revealed that following downregulation of podocyte markers, podocytes were progressively lost, without transforming into other types of cell. Studies using chimeric mice revealed that injury initiated in a portion of podocytes was spread to other podocytes, thus forming a vicious cycle of self-perpetuating injury.
Using other transgenic mouse lines that we developed, we demonstrated that in the presence of FVB/N genetic background, HIV-1 genes, vpr and nef, synergistically damage podocytes, leading to collapsing FSGS similar to HIV-1 associated nephropathy of humans.
In both NEP25 and HIV-1 models, damage of podocytes was prevented remarkably by ureteral obstruction, indicating that continued glomerular filtration is a prerequisite for progressive injury of podocytes, and subsequent development of glomerular sclerosis.
We also studied the role of mutant α-Actinin-4, which causes autosomal dominant focal segmental glomerular sclerosis (FSGS) in humans. Transgenic mice expressing mutant α-Actinin-4 in podocytes developed slowly progressive FSGS. By crossing α-Actinin-4 with NEP25 mice, we demonstrated that mutant α-Actinin-4 attenuated glomerular damage induced by LMB2.
Thus, we demonstrated that in the presence of glomerular filtration, podocyte damage induced by various factors is automatically spread to other podocytes and types of cell within the glomerulus, which leads to glomerular sclerosis.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (23 results)

All 2006 2005 2004 2003 Other

All Journal Article (19 results) Publications (4 results)

  • [Journal Article] Inhibition of endogenous BMP in the glomerulus leads to mesangial matrix expansion.2006

    • Author(s)
      Miyazaki Y, Ueda H, Yokoo T, Utsunomiya Y, Kawamura T, Matsusaka T, Ichikawa I, Hosoya T.
    • Journal Title

      Biochem Biophys Res Commun. 340(2)

      Pages: 681-688

    • 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] 糸球体内皮細胞2006

    • Author(s)
      浅野貴子, 松阪泰二
    • Journal Title

      日本臨牀 64 Supple2

      Pages: 74-78

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Structure and function of glomerular endothelial cells2006

    • Author(s)
      Asano T, Matsusaka T.
    • Journal Title

      Nippon Rinsho. 64 Supple 2

      Pages: 74-78

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Genetic engineering of glomerular sclerosis in the mouse via control of onset and severity of podocyte-specific injury.2005

    • Author(s)
      Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang QC, Pastan I, Fogo AB, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol. 16(4)

      Pages: 1013-1023

    • 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 HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy.2005

    • Author(s)
      Zhong J, Zuo Y, Ma J, Fogo AB, Jolicoeur P, Ichikawa I, Matsusaka T.
    • Journal Title

      Kidney Int. 68(3)

      Pages: 1048-1060

    • 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] Permanent genetic tagging of podocytes : fate of injured podocytes in a mouse model of glomerular sclerosis.2005

    • Author(s)
      Asano T, Niimura F, Pastan I, Fogo AB, Ichikawa I, Matsusaka T.
    • Journal Title

      J Am Soc Nephrol. 16(8)

      Pages: 2257-2262

    • 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] Podocyte damage damages podocytes : autonomous vicious cycle that drives local spread of glomerular sclerosis.2005

    • Author(s)
      Ichikawa I, Ma J, Motojima M, Matsusaka T
    • Journal Title

      Curr Opin Nephrol Hypertens. 14(3)

      Pages: 205-210

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A role of BMP in the development of glomerular sclerosis.2005

    • Author(s)
      Ueda H, Miyazaki Y, Yokoo T, Utsunomiya Y, Kawamura T, Matsusaka T, Ichikawa I, Hosoya T.
    • Journal Title

      Nephrology (Carlton). 10 Supple6

    • 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] Podocyte damage damages podocytes : autonomous vicious cycle that drives local spread of glomerular sclerosis.2005

    • Author(s)
      Ichikawa I, Ma J, Motojima M, Matsusaka T.
    • Journal Title

      Curr Opin Nephrol Hypertens. 14(3)

      Pages: 205-210

    • 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] Local actions of endogenous angiotensin II in injured glomeruli.2004

    • Author(s)
      Ma J, Matsusaka T, Yang H, Kawachi H, Shimizu F, Isaka Y, Imai E, Kon V, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol. 15(5)

      Pages: 1268-1276

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 糸球体上皮細胞傷害と糸球体硬化2004

    • Author(s)
      松坂泰二
    • Journal Title

      日本臨牀 62(10)

      Pages: 1805-1810

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Podocyte injury and glomerular sclerosis.2004

    • Author(s)
      Matsusaka T.
    • Journal Title

      Nippon Rinsho. 62(20)

      Pages: 1805-1810

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Local actions of endogenous angiotensin II in injured glomeruli.2004

    • Author(s)
      Ma J, Matsusaka T, Yang H, Kawachi H, Shimizu F, Isaka Y, Imai E, Kon V, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol 15(5)

      Pages: 1268-1276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interruption of Glomerular Filtation Interrupts the Pathogenic Pathway from Podocyte Injury to Glomerular Sclerosis.2004

    • Author(s)
      Matsusaka T, Fogo A, Pastan I, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol 15

    • Related Report
      2004 Annual Research Report
  • [Journal Article] HIV-1 Genes vpr and nef Synergistically Cause Podocyte Injury.2004

    • Author(s)
      Zuo Y, Zhong J, Ma J, Fogo A, Ichikawa I, Matsusaka T.
    • Journal Title

      J Am Soc Nephrol 15

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identity of the Origin of Proliferating Visceral Epithelial Cells.2004

    • Author(s)
      Asano T, Matsusaka T, Fogo A, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol 15

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ポドサイトバイオロジー、ノックアウト・トランスジェニックマウス研究から得られた知見2003

    • Author(s)
      松坂泰二
    • Journal Title

      腎と透析 55(5)

      Pages: 735-741

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Podocyte biology, insights from knock-out and transgenic mouse studies2003

    • Author(s)
      Matsusaka T.
    • Journal Title

      Jin To Toseki. 55(5)

      Pages: 735-741

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Genetic engineering of glomerular sclerosis in the mouse via control of onset and of severity of podocyte-specific injury.

    • Author(s)
      Matsusaka T, Xin J, Niwa S, Kobayashi K, Akatsuka A, Hashizume H, Wang QC, Pastan I, Fogo A, Ichikawa I.
    • Journal Title

      J Am Soc Nephrol (in press)

    • Related Report
      2004 Annual Research Report
  • [Publications] J Zhong, A Fogo, I Ichikawa, T Matsusaka: "Role of Angiotensin II the Development of Focal Segmental Glomerulosclerosis (FSGS) in Human Immunodeficiency Virus (HIV)-1 Associated Nephropathy (HIVAN)."J Am Soc Nephrol (abstract). 14. 153A (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] J Zhong, Y Zuo, J Ma, A Fogo, I Ichikawa, T Matsusaka: "Expression of HIV-1 Genes in Podocytes Alone Can Lead to Glomerulosclerosis."J Am Soc Nephrol (abstract). 14. 153A (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] T Matsusaka, A Fogo, J Xin, I Ichikawa: "Podocyte Injury Is a Key to the Vicious Cycle of Progressive Glomerular Damage Leading to Renal Failure."J Am Soc Nephrol (abstract). 14. 156A (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] J Xin, A Fogo, T Matsusaka, I Ichikawa: "Podocyte Injury-Triggered Progressive Glomerular Deterioration Is Attenuated by Inhibition of Type 1 Angiotensin II Receptor (AT1)."J Am Soc Nephrol (abstract). 14. 157A (2003)

    • Related Report
      2003 Annual Research Report

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

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