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Progression of kidney fibrosis and ubiquitin-proteasome degradation of inhibitory factors for Smad-TGF-p signaling

Research Project

Project/Area Number 17590824
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

TATSUO Yamamoto  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)
FUKASAWA Hirotaka  Hamamatsu University School of Medicine, Senior resident, 医学部附属病院, 医員 (60397370)
OHASHI Naro  Hamamatsu University School of Medicine, Senior resident, 医学部, 医員 (50397387)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsubiquitin / SnoN / Ski / TGF-p / kidney fibrosis / intracellular signaling / Smad
Research Abstract

We investigated the expression, degradation and ubiquitination of inhibitory Smad7 and Smad transcriptional co-repressors SnoN (ski-related novel gene N) and Ski (Sloan-Kettering Institute proto-oncogene) in the fibrotic kidneys of C57BL6/J mice with unilateral ureteral obstruction (UUO). We found the following results.
1.Increased mRNA expression of TGF-p, type IV collagen, Smad7, SnoN, and Ski was detected by real time RT-PCR in the fibrotic obstructed kidneys, while western blot analysis revealed the decreases in Smad7, SnoN and Ski proteins.
2.Increased degradation of endogenous Smad7, SnoN and Ski proteins was noted in the renal extracts prepared from the obstructed kidneys by degradation assay.
3.Increased ubiquitination activity directed against exogenous recombinant Smad7, SnoN and Ski proteins was noted in the renal extracts prepared from the obstructed kidneys by ubiquitination assay.
4.Immunodepletion of Smurf2 in extracts of obstructed kidneys resulted in reduced ubiquitination of Smad7 and SnoN, while no significant changes were noted in the ubiquitination of Ski.
5.Increased expression of Smurf2 mRNA and protein was noted in the obstructed kidneys by real time RT-PCR and western blot analysis, respectively.
6.These data suggest that the reduction of Smad7, SnoN and Ski proteins resulting from increased ubiquitin-dependent degradation is involved in the progression of tubulointerstitial fibrosis after obstructive injury. It was also demonstrated that the ubiquitination activity directed against Smad7 and SnoN, but not Ski, was at least partially mediated by Smurf2 in UUO-induced fibrotic kidneys.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (21 results)

All 2007 2006 2005

All Journal Article (21 results)

  • [Journal Article] Urinary angiotensinogen as a marker of intrarenal angiotensin ii activity associated with deterioration of renal function in patients with chronic kidney disease.2007

    • Author(s)
      Tatsuo Yamamoto
    • Journal Title

      J. Am. Soc. Nephrol. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Urinary angiotensinogen as a marker of intrarenal angiotensin ii activity associated with deterioration of renal function in patients with chronic kidney disease.2007

    • Author(s)
      Tatsuo Yamamoto, et al.
    • Journal Title

      J. Am. Soc. Nephrol. 18-5

      Pages: 1558-1565

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Urinary angiotensinogen as a marker of intrarenal angiotensin ii activity associated with deterioration of renal function in patients with chronic kidney disease.2007

    • Author(s)
      Tatsuo Yamamoto
    • Journal Title

      J. Am. Soc. Nephrol. 18・5

      Pages: 1558-1565

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.2006

    • Author(s)
      Hirotaka Fukasawa
    • Journal Title

      Kidney Int. 69・10

      Pages: 1733-1744

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Increased reactive oxygen species contributes to kidney injury in mineralocorticoid hypertensive rats.2006

    • Author(s)
      Liming Jin
    • Journal Title

      J. Physiol. Pharmacol. 57・3

      Pages: 343-357

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Kinetics and characterization of initially regenerating proximal tubules in S3 segment in response to various degrees of acute tubular injury.2006

    • Author(s)
      Yoshihide Fujigaki
    • Journal Title

      Nephrol. Dial. Transplant. 21・1

      Pages: 41-50

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Urinary marker for oxidative stress in kidneys in cisplatin-induced acute renal failure in rats.2006

    • Author(s)
      Hau Zhou
    • Journal Title

      Nephrol. Dial. Transplant. 21・3

      Pages: 616-623

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats.2006

    • Author(s)
      Hau Zhou
    • Journal Title

      Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats. 291・1

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Ubiquitin-dependent degradation of SnoN and Ski is increased in renal fibrosis induced by obstructive injury.2006

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

      Kidney Int. 69-10

      Pages: 1733-1744

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Increased reactive oxygen species contributes to kidney injury in mineralocorticoid hypertensive rats.2006

    • Author(s)
      Liming Jin, et al.
    • Journal Title

      J. Physiol. Pharmacol. 57-3

      Pages: 343-357

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Kinetics and characterization of initially regenerating proximal tubules in S3 segment in response to various degrees of acute tubular injury.2006

    • Author(s)
      Yoshihide Fujigaki, et al.
    • Journal Title

      Nephrol. Dial. Transplant. 21-1

      Pages: 41-50

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Urinary marker for oxidative stress in kidneys in cisplatin-induced acute renal failure in rats.2006

    • Author(s)
      Hau Zhou, et al.
    • Journal Title

      Nephrol. Dial. Transplant. 21-3

      Pages: 616-623

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats.2006

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

      Am. J. Physiol. Renal Physiol. 291-1

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats.2006

    • Author(s)
      Hau Zhou
    • Journal Title

      Am. J. Physiol. Renal Physiol. 291・1

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta.2005

    • Author(s)
      Naro Ohashi
    • Journal Title

      FEBS Lett. 579・12

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats.2005

    • Author(s)
      Yoshihide Fujigaki
    • Journal Title

      Virchows Arch. 446・2

      Pages: 164-176

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] High dose chemotherapy and stem cell support in a patient of light- and heavy-chain deposition disease with abnormal marrow cell surface antigens and no monoclonal protein.2005

    • Author(s)
      Masanori Sakakima
    • Journal Title

      Intern. Med. 44・9

      Pages: 970-974

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Transcriptional induction o : Smurf2 ubiquitin ligase by TGF-beta.2005

    • Author(s)
      Naro Ohashi, et al.
    • Journal Title

      FEBS Lett. 579-12

      Pages: 2557-2563

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transient myofibroblast differentiation of interstitial fibroblastic cells relevant to tubular dilatation in uranyl acetate-induced acute renal failure in rats.2005

    • Author(s)
      Yoshihide Fujigaki, et al.
    • Journal Title

      Virchows Arch. 446-2

      Pages: 164-176

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] High dose chemotherapy and stem cell support in a patient of light-and heavy-chain deposition disease with abnormal marrow cell surface antigens and no monoclonal protein.2005

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

      Intern. Med. 44-9

      Pages: 970-974

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Transcriptional induction of Smurf2 ubiquitin ligase by PGF-beta.2005

    • Author(s)
      Ohashi N, Yamamoto T, Uchida C, Togawa A, Fukasawa H, Fujigaki Y, Suzuki S, Kitagawa K, Hattori T, Oda T, Hayashi H, Hishida A, Kitagawa M.
    • Journal Title

      FEES Lett. 579・2

      Pages: 2557-2563

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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