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The elucidation of the mechanisms underlying contrast media induced nephrotoxicity and its prophylaxis.

阐明造影剂诱发肾毒性的机制及其预防。

基本信息

批准号：
17590471
负责人：
OISHI Ryozo
金额：
$ 2.24万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590471/
关键词：
contrast media nephrotoxicity apoptosis ceramide cyclic AMP prostacyclin ヨード造影剤

项目摘要

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.

放射性造影剂（RCM）是引起药物性急性肾功能衰竭的主要原因之一，但其细胞机制尚不完全清楚。我们研究了RCM诱导肾小管细胞凋亡，其中涉及bcl-2 mRNA的降低和随后的caspase-9和caspase-3的激活。此外，发现RCM诱导的Bcl-2表达减少是通过磷酸化Akt（pAkt）和环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）磷酸化的减少介导的。各种RCM均可增加肾小管细胞神经酰胺含量，其增加与细胞活力丧失密切相关。由RCM诱导的神经酰胺含量的升高和细胞损伤均被伏马菌素Bl逆转，但不被D 609逆转，表明神经酰胺从头合成的作用。与RCM一样，神经酰胺降低pAkt，降低Bcl-2表达，增强caspase-9和caspase-3活性，并导致细胞凋亡。在小鼠RCM肾病模型中也观察到伏马菌素B1的体内保护作用。此外，前列环素类似物贝前列素诱导内源性cAMP升高可有效预防放射造影剂肾病，其中涉及A激酶/PI 3-激酶/Akt激活和CREB磷酸化，这些发现表明神经酰胺合成抑制剂或贝前列素可能用于预防放射造影剂肾毒性。