• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Development of the treatment of diabetic nephropathy by targeting the TGF-β signaling

Research Project

Project/Area Number 12470227
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionShiga University of Medical Science

Principal Investigator

KIKKAWA Ryuichi  Shiga Univ.of Medical Science President, 医学部, 学長 (50093406)

Co-Investigator(Kenkyū-buntansha) KOYA Daisuke  Shiga University of Medical Science, Assistant Professor, 医学部, 助手 (70242980)
HANEDA Masakazu  Shiga University of Medical Science, Associate Professor, 医学部, 講師 (60164894)
前川 聡  滋賀医科大学, 医学部, 助手 (00209363)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2002: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥8,400,000 (Direct Cost: ¥8,400,000)
Keywordsmesangial cells / TGF-β / Smad / Ac-SDKP / pioglitazone / fibronectin / AP-1 / 糖尿病性腎症 / 細胞外基質 / MAPKs
Research Abstract

Diabetic nephropathy is characterized by an accumulation of extracellular matrix (ECM) proteins. TGF-β is a key cytokine which mediates the progression of diabetic nephropathy. In this study, we examined the intracellular mechanism by which TGF-β-induced ECM proteins such as fibronectin, one of the major ECM proteins accumulated in renal glumeruli. We also examined the effects of pioglitazone, new insulin sensitizing agent, and N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) which was increased by the treatment of angiotensin converting enzyme inhibitors on TGF-β-induced ECM expression and intracellular signaling pathways. In cultured mesangial cells, TGF-β1 stimulated nuclear translocation of Smad2, 3, 4 and activated ERK and JNK. TGF-β1 induced fibronectin mRNA expression, and this was inhibited by a specific MEK inhibitor, PD98059 without affecting Smad signaling. These results suggest that MEK-ERK pathway is required for TGF-β-induced fibronectin expression. Pioglitazone inhibited TGF-β1-induced fibronectin expression by inhibiting TGF-β-inducedAP-1 but not ERK activation. Ac-SDKP inhibited TGF-β-induced PAI-1 and type I collagen expressions. Ac-SDKP inhibited activation of Smad2, 3 and SBE reporter activity by TGF-β1. The overexpressed Smad7 was translocated from the nucleus to the cytosol by Ac-SDKP, suggesting that Ac-SDKP inhibited Smad signaling via Smad7 translocation. These results provide novel evidence that pioglitazone and Ac-SDKP has an antifibrotic effect, and inhibiting the TGF-β signaling by these agents could be a useful therapy to diabetic nephropathy.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] Inoki K, Haneda M, Ishida T, Mori H, Maeda S, Koya D, Sugimoto T, Kikkawa R: "Role of mitogen-activated protein kinases as downstream effectors of transforming growth factor-beta in mesangial cells"Kidney International. 58. S76-S80 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishio T, Haneda M, Koya D, Inoki K, Maeda S, Kikkawa R: "Cyclic AMP inhibits stretch-induced overexpression of fibronectin in glomerular mesangial cells"European Journal of Pharmacology. 437. 113-122 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sawano H, Habeda M, Sugimoto T, Inoki K, Koya D, Kikkawa R: "15-Deoxy-Delta 12,14-prostaglandin J2 inhibits IL-1 beta-induced cyclooxgenase-2 expression in mesangial cells"Kidney International. 61. 1957-1967 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanasaki K, Koya D, Sugimoto T, Isono M, Kashiwagi A, Haneda M: "N-Acetyl-Seryl-Aspartyl-Lysyl-Proline inhibits TGF-β-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells"Journal of the American Society of Nephrology. 14. 863-872 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haneda M, Koya D, Isono M, Kikkawa R: "Overview of glucose signaling in mesangial cells in diabetic nephropathy"Journal of the American Society of Nephrology. 14. 1374-1382 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Inoki K, Haneda M, Ishida T, Mori H, Maeda S, Koya D, Sugimoto T, Kikkawa R: "Role of mitogen-activated protein kinases as downstream effectors of transforming growth factor-beta in mesangial cells"Kidney Int. 77, suppl.. S76-S80 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishio T, Haneda M, Koya D, Inoki K, Maeda S, Kikkawa R: "Cyclic AMP inhibits stretch-induced overexpression of fibronectin in glomerular mesangial cells"Eur J Pharmacol. 437. 113-122 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sawano H, Habeda M, Sugimoto T, Inoki K, Koya D, Kikkawa R: "15-Deoxy-Delta 12, 14-prostaglandin J2 inhibits IL-1 beta-induced cyclooxgenase-2 expression in mesangial cells"Kdney Int. 61. 1957-1967 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanasaki K, Koya D, Sugimoto T, Isono M, Kashiwagi A, Haneda M: "N-Acetyl-Seryl-Aspartyl- Lysyl-Proline inhibits TGF-β-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells"J Am Soc Nephrol. 14. 863-872 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haneda M, Koya D, Isono M, Kikkawa: "Overview of glucose signaling in mesangial cells in diabetic nephropathy"Am Soc Nephrol. 14. 1374-1382 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kanasaki K, Koya D, Sugimoto T, Isono M, Kashiwagi A, Haneda M: "N-Acetyl-Seryl-Aspartyl-Lysyl-Proline inhibits TGF-b-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells"Journal of the American Society of Nephrology. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Inoki K et al.: "Role of mitogen-activated protein kinases as downstream effectors of transforming growth factor-βin mesangial cells"Kidney International. 58,Suppl.77. S76-S80 (2000)

    • Related Report
      2000 Annual Research Report

URL: 

Published: 2000-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi