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The role of NF-kB in the pathogenesis of glomerulonephritis and therapeutic strategy through its regulation.

Research Project

Project/Area Number 09671167
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionKAWASAKI MEDICAL SCHOOL (1998)
Okayama University (1997)

Principal Investigator

KASHIHARA Naoki  Kawasaki Medical School, Medicine , Professor, 医学部, 教授 (10233701)

Co-Investigator(Kenkyū-buntansha) 山村 昌弘  岡山大学, 医学部附属病院, 講師 (80252956)
槇野 博史  岡山大学, 医学部, 教授 (50165685)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsNF-kB / Glomerulonephritis / Glucocorticoid / 転写因子 / ケモカイン / サイトカイン
Research Abstract

NF-kB is a pleiotrophic transcription factor, which activate a number of cytokines, growth factors and adhesion molecules, which are implicated in cellular response to injury , such as mesangial cell (MC) proliferation or infiltration of inflammatory cells, in glomerulonephritis. We attempted to inhibit NF-kB activity by using glucocorticoid, anti-oxidant (PDTC), and oligonucleotide (ODN) which contains the consensus NF-kB binding site (decoy DNA) and evaluated inhibitory effect on mesangial cell proliferation in vitro and therapeutic effects in the rat anti-Thy1.1 nephritis model as well. First, the effect of these three reagents on MC proliferation was assessed in vitro. The nuclear extracts were prepared from the cells treated with these reagents. Electrophoretic mobility-shift assay (EMSA) was performed to confirm the effect on NF-kB DNA binding activity. Secondly, these three reagents were used in vivo. The rat anti-Thy1.1 model was induced by injection of monoclonal anti-Thy1.1 a … More ntibody (oX-7). At day 2, Renal biopsy was performed at day 8. The total cell number and the number of proliferating nuclear cell antigen (PCNA)-positive cells per glomerular cross section were determined. Glomerular mRNA was extracted and the mRNA expressions of IL-1, TNF-a, MCP-1 and ICAM-1 of which gene expression was regulated by NF-kB, were measured by reverse transcriptase polymerase chain reaction (RT-PCR) method. NF-kB decoy inhibited the MC growth in a dose dependent manner in vitro. Ten mM of decoy inhibited the MC growth by 75%. EMSA revealed that this inhibitory effect was mediated by decreased NF-kB binding activity. Glucocorticoid, PDTC and NF-kB decoy suppressed MC proliferation in the Thy1.1 glomerulonephritis model. The number of glomerular cell decreased by 25%. Decreased mRNA expressions of IL-1, TNF-a, MCP-1 and ICAM-1 were recognized in the experimental group. Thus, inhibition of mesangial cell proliferation was possibly resulted from suppressed expression of these cytokines at least in part. These results suggest the feasibility of the reagents targeting NF-kB funtion as a novel therapeutic agent for glomerular diseases. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] 柏原直樹: "Antisense oligonucleotides"Exp Nephrol. 6. 84-88 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 柏原直樹: "Apoptosis and scarring"Clin Exp Nephrol. 2. 302-306 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 前島洋平: "Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo"J Clin Invest. 101. 2589-2597 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 杉山 斉: "Regulation of survival and death of mesangial cells by extracellular matrix"Kidney Int. 54. 1186-1196 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 杉山 斉: "Bcl-2 expression and apoptosis in nephrotoxic nephritis"Exp Nephrol. 5. 481-489 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 柏原直樹: "Therapeutic intervention in glomerulonephritis by oligonucleotides"Exp Nephrol. 5. 126-131 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kashihara N, Maeshima Y, and Makino H: "Antisense oligonucleotides"Exp Nephrol. 6. 84-88 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kashihara N, Sugiyama H, and Makino H: "Apoptosis and scarring"Clin Exp Nephrol. 2. 302-306 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Maeshima Y, Kashihara N, Yasuda T, Sugiyama H, Sekikawa T, Okamoto K, Kanao K, Watanabe Y, Kanwar Y S, and Makino H: "Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo"J Clin Invest. 101. 2589-2597 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sugiyama H, Kashihara N, Maeshima Y, Okamoto K, Kanao K, Sekikawa T, and Makino H: "Regulation of survival and death of mesangial cells by extracellular matrix"Kidney Int. 54. 1188-1196 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sugiyama H, Kashihara N, Onbe T, Yamasaki Y, Wada J, Sekikawa T, Okamoto K, Kanao K, Maeshima Y, and Makino H: "Bcl-2 expression and apoptosis in nephrotoxic nephritis"Exp Nephrol. 5. 481-489 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kashihara N, Maeshima Y, and Makino H: "Therapeutic intervention in glomerulonephritis by oligonucleotides"Exp Nephrol. 5. 126-131 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 柏原直樹: "Antisense oligonucleotides." Exp Nephrol. 6. 84-88 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 柏原直樹: "Apoptpsis and scarring." Clin Exp Nephrol. 2. 302-306 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 前島洋平: "Inhibition of mesangial cell proliferation by E2F decoy oligodeoxynucleotide in vitro and in vivo." J Clin Invest. 101. 2589-2597 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 杉山 斉: "Regulation of survival and death of mesangial cells by extracellular matrix" Kidney Int. 54. 1186-1196 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 杉山 斉: "Bc1-2 expression and apoptosis in nephrotoxic nephritis." Exp Nephrol. 5. 481-489 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 柏原直樹: "Therapeutic intervention in glomerulonephritis by oligonucleotides." Exp Nephrol. 5. 126-131 (1997)

    • Related Report
      1998 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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