2006 Fiscal Year Final Research Report Summary
The elucidation of the mechanisms underlying contrast media induced nephrotoxicity and its prophylaxis.
| Project/Area Number |
17590471
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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 |
Applied pharmacology
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| Research Institution | KYUSHU UNIVERCITY |
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Principal Investigator |
OISHI Ryozo Kyushu University, Hospital, Professor, 大学病院, 教授 (90112325)
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| Co-Investigator(Kenkyū-buntansha) |
ITOH Yoshinori Gifu University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (50159927)
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| Project Period (FY) |
2005 – 2006
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| Keywords | contrast media / nephrotoxicity / apoptosis / ceramide / cyclic AMP / prostacyclin |
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| Research Abstract |
Radiographic contrast medium (RCM) is one of major causes of drug-induced acute renal failure, although the cellular mechanisms are not fully understood. We investigated that RCM induces apoptosis in renal tubular cells, in which decrease in bcl-2 mRNA and subsequent activation of caspase-9 and caspase-3 are involved. Moreover, RCM-induced reduction in Bcl-2 expression was found to be mediated by decrease in phosphorylated Akt (pAkt) and cyclic AMP (cAMP)-responsive element binding protein (CREB) phosphorilation. Various RCM increased ceramide content in renal tubular cells, in which the increase was closely related to the loss of cell viability. Both the elevation of ceramide content and cell injury induced by RCM were reversed by fumonisin Bl but not D609, suggesting a role for de novo ceramide synthesis. Like RCM, ceramide decreased pAkt, reduced Bcl-2 expression, enhanced caspase-9 and caspase-3 activities, and led to apoptosis. The protective effect of fumonisin Bl was also observed in vivo in murine model of RCM nephropathy. Moreover, a prostacyclin analog beraprost induce the elevation of endogenous cAMP effectively prevents radiocontrast nephropathy, in which activation of A kinase/PI 3-kinase/Akt followed by CREB phosphorylation are involved.
These findings suggest that ceramide synthesis inhibitor or beraprost may be potentially useful for the prophylaxis of radiographic contrast media nephrotoxicity.
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