2006 Fiscal Year Final Research Report Summary
Protective roles for cyclic AMP and its analogs against cisplatin-induced nephropathy
| Project/Area Number |
17590129
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Gifu University (2006)
Kyushu University (2005) |
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Principal Investigator |
ITOH Yoshinori Gifu University, Graduates School of Medicine, Professor, 大学院医学系研究科, 教授 (50159927)
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| Co-Investigator(Kenkyū-buntansha) |
OISHI Ryozo Kyushu University, University Hospital, Professor, 大学病院, 教授 (90112325)
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| Project Period (FY) |
2005 – 2006
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| Keywords | cisplatin / renal toxicity / apoptosis / necrosis / caspases / TNF-α / p53 / cyclic AMP |
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| 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
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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
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