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The role of ubiquitin-proteasome degradation pathway in TGF-β-Smad signaling in kidney diseases

Research Project

Project/Area Number 15590847
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

YAMAMOTO Tatsuo  Hamamatsu University School of Medicine, Assistant Professor, 医学部附属病院, 講師 (30200819)

Co-Investigator(Kenkyū-buntansha) KITAGAWA Masatoshi  Hamamatsu University School of Medicine, Professor, 医学部, 教授 (50294971)
FUJIGAKII Yoshihide  Hamamatsu University School of Medicine, Instructor, 医学部, 助手 (20283351)
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: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordsubiquitin / Smad / TGF-β / Smurf / kidney fibrosis / intracellular signaling
Research Abstract

We investigated the levels of Smads that mediate the intracellular TGF-β signaling and the activity of ubiquitin-proteasome degradation directed to Smads in isolated glomeruli from rats with anti-thymocyte serum (ATS) nephritis, a model of mesangial proliferative glomerulonephritis, and mice kidneys receiving unilateral ureteral obstruction (UUO), a model of progressive tubulointerstitial fibrosis. We found the following results.
1.Smad2 protein was decreased markedly in ATS nephritic glomeruli and UUO kidneys, while Smad2 mRNA expression did not change in the former and increased in the latter, suggesting the involvement of Smad2-specific degradation mechanism in these lesions.
2.Increases in degradation of intrinsic Smad2 protein and ubiquitination activity against Smad2 were noted in ATS nephritic glomeruli and UUO kidneys, and the degradation of Smad2 was blocked by a proteasome inhibitor.
3.We cloned the rat Smurf2, an E3 ubiquitin ligase for Smad2.
4.Increases in Smurf2 protein and mRNA were noted in ATS nephritic glomeruli and UUO kidneys.
5.The decrease of inhibitory Smad7 protein and the enhanced ubiquitination and degradation of Smad7 protein were noted in UUO kidneys, in which the expression of Smad7 mRNA increased.
6.The degradation of Smad7 in UUO kidneys was inhibited by a proteasome inhibitor.
These data suggest that the increase of the selective ubiquitin-dependent degradation of Smad2 mediated by Smurf2 results in relative predominance of Smad3-mediated TGF-β signaling in ATS nephritic glomeruli and UUO kidneys. The decrease of inhibitory Smad7 resulted from enhanced ubiquitin-dependent degradation may also be involved in the progression of tubulointerstitial fibrosis in UUO kidneys, in which uncontrolled overexpression of TGF-β activity plays a pathogenic role.

Report

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

    (21 results)

All 2004 2003 Other

All Journal Article (18 results) Publications (3 results)

  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Hirotaka Fukasawa
    • Journal Title

      Kidney Int. 65

      Pages: 63-74

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dietary salt intake modulates progression of anti-thymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression.2004

    • Author(s)
      Hiroyuki Suzuki
    • Journal Title

      Am.J.Physiol. 286

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Down regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.2004

    • Author(s)
      Hirotaka Fukasawa
    • Journal Title

      Proc Natl Acad Sci USA 101

      Pages: 8687-8692

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase inductionin gentamicin-induced acute renal failure in rats.2004

    • Author(s)
      Tetsuo Goto
    • Journal Title

      Virchows Arch 444

      Pages: 362-374

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure.2004

    • Author(s)
      Hua Zhou
    • Journal Title

      Toxicol Appl Pharmacol 200

      Pages: 111-120

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Hirotaka Fukasawa et al.
    • Journal Title

      Kidney Int. 65

      Pages: 63-74

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Dietary salt intake modulates progression of anti-thymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression.2004

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

      Am.J.Physiol. 286

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Down regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.2004

    • Author(s)
      Hirotaka Fukasawa et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 101

      Pages: 8687-8692

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase inductionin gentamicin-induced acute renal failure in rats.2004

    • Author(s)
      Tetsuo Goto et al.
    • Journal Title

      Virchow Arch. 444

      Pages: 362-374

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The induction of cell cycle regulatory and DNA proteins in cisplatin-induced acute renal failure.2004

    • Author(s)
      Hua Zhou et al.
    • Journal Title

      Toxicol.Appl.Pharmacol. 200 : repair

      Pages: 111-120

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling.2004

    • Author(s)
      Hirotaka Fukasawa
    • Journal Title

      Kidney Int. 65・1

      Pages: 63-74

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dietary salt intake modulates progression of anti-thymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression.2004

    • Author(s)
      Hiroyuki Suzuki
    • Journal Title

      Am.J.Physiol. 286・2

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Down regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice.2004

    • Author(s)
      Hirotaka Fukasawa
    • Journal Title

      Proc Natl Acad Sci USA 101・23

      Pages: 8687-8692

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Plasma protein extravasation and vascular endothelial growth factor expression with endothelial nitric oxide synthase inductionin gentamicin-induced acute renal failure in rats.2004

    • Author(s)
      Tetsuo Goto
    • Journal Title

      Virchows Arch 444・4

      Pages: 362-374

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The induction of cell cycle regulatory and DNA repair proteins in cisplatin-induced acute renal failure.2004

    • Author(s)
      Hua Zhou
    • Journal Title

      Toxicol Appl Pharmacol 200・2

      Pages: 111-120

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis.2003

    • Author(s)
      Akashi Togawa
    • Journal Title

      Am.J.Pathol. 163

      Pages: 1645-1652

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis.2003

    • Author(s)
      Akashi Togawa et al.
    • Journal Title

      Am.J.Pathol. 163

      Pages: 1645-1652

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis.2003

    • Author(s)
      Akashi Togawa
    • Journal Title

      Am.J.Pathol. 163・4

      Pages: 1645-1652

    • Related Report
      2004 Annual Research Report
  • [Publications] Togawa A, Yamamoto T, Suzuki H, Fukasawa H, Ohashi N, Fujigaki Y, Kitagawa K, Hattori T, Kitaqawa M, Hishida A: "Ubiquitin-dependent degradation of Smad2 is increased in the glomeruli of rats with anti-thymocyte serum nephritis"Am.J.Pathol.. 163・4. 1645-1652 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fukasawa H, Yamamoto T, Suzuki H, Togawa A, Ohashi N, Fujigaki Y, Uchida C, Aoki M, Hosono M, Kitagawa M, Hishida A: "Treatment with anti-TGF-β antibody ameliorates chronic progressive nephritis by inhibiting Smad/TGF-β signaling"Kidney Int.. 65・1. 63-74 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki H, Yamamoto T, Ikegaya N, Hishida A: "Dietary salt intake modulates progression of anti-thymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression"Am.J.Physiol.. 286・2. F267-F277 (2004)

    • Related Report
      2003 Annual Research Report

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

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