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Protective roles for cyclic AMP and its analogs against cisplatin-induced nephropathy

Research Project

Project/Area Number 17590129
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionGifu University (2006)
Kyushu University (2005)

Principal Investigator

ITOH Yoshinori  Gifu University, Graduates School of Medicine, Professor, 大学院医学系研究科, 教授 (50159927)

Co-Investigator(Kenkyū-buntansha) OISHI Ryozo  Kyushu University, University Hospital, Professor, 大学病院, 教授 (90112325)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥2,500,000 (Direct Cost: ¥2,500,000)
Keywordscisplatin / renal toxicity / apoptosis / necrosis / caspases / TNF-α / p53 / cyclic AMP / p38MAPキナーゼ / サイクリックAMP / 活性酸素種
Research Abstract

The protective roles for cyclic AMP and its analogs were determined in the in vitro as well as in vivo models of, cisplatin-induced nephropathy. The transient exposure of a porcine renal tubular cell line LLC-PK_1, cells to a high concentration of cisplatin caused necrosis, in which reduction in superoxide dismutase activity as well as lipid peroxidation and subsequent enhancement of TNF-α production through phosphorylation of p38 MAPK were observed. These cellular events and necrosis were prevented by antioxidants. On the other hand, cAMP analog DBcAMP and a prostacyclin analog beraprost revealed protective effect against cisplatin-induced renal toxicity by inhibiting lipid peroxidation and TNF-a synthesis. In rats, cisplatin caused the increase in serum creatinine and blood urea nitrogen, renal tubular injury characterized by protein casts and elevation of tissue TNF-a content. These events were reversed by systemic administration of beraprost. On the other hand, a few TUNEL-positive … More cells were observed in tubular cells of cisplatin-treated rats, suggesting a role for apoptosis. Subsequently, we established in vitro model of cisplatin-induced nephropathy, in which both apoptosis and necrosis are implicated. The exposure of LLC-PK1 cells to 200 μM cisplatin for 1 h followed by incubation with 20 μM cisplatin for 12-24 h induced necrosis and apoptosis. Oxidative stress was involved in the former, while activation of caspases was implicated in the latter. In addtion, activations of caspases-2, -8, -9 and -3 were observed after exposure to cisplatin, in which activation of caspase-2 stimulated the activities of caspases-8 and-9 and ultimately caspase-3. Moreover, the activation of caspase-2 was inhibited by pifithrin-a, indicating a role for p53.
From these findings, it is suggested that phosphorylation of p38 MAPK and TNF-α production by an excessive production of reactive oxygen species are implicated in the pathogenesis of cisplatin-induced necrosis, while p53-mediated activation of several classes of caspases contributes to the apoptosis associated with cisplatin nephropathy. Less

Report

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

    (4 results)

All 2006 Other

All Journal Article (4 results)

  • [Journal Article] Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity2006

    • Author(s)
      Mishima K., Baba A., Matsuo M., Itoh Y., Oishi R.
    • Journal Title

      Free Radical Biology & Medicine 40・9

      Pages: 1564-1577

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity2006

    • Author(s)
      Mishima K., Baba A, Matsuo M., Itoh Y, Oishi R.
    • Journal Title

      Free Radical Biology & Medicine 40-9

      Pages: 1564-1577

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity2006

    • Author(s)
      Mishima K et al.
    • Journal Title

      Free Radical Biology & Medicine 40・9

      Pages: 1564-1577

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Protective effect of cyclic AMP against cisplatin-induced nephrotoxicity

    • Author(s)
      Mishima K et al.
    • Journal Title

      Free Radical Biology & Medicine (in press)

    • Related Report
      2005 Annual Research Report

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

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