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

放射造影剂（RCM）是药物性急性肾功能衰竭的主要原因之一，尽管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的减少和随后caspase-9和caspase-3的激活。此外，rcm诱导的Bcl-2表达降低是通过磷酸化Akt （pAkt）和环AMP （cAMP）响应元件结合蛋白（CREB）磷酸化的降低介导的。各种RCM使肾小管细胞神经酰胺含量增加，其增加与细胞活力丧失密切相关。伏马菌素Bl可逆转神经酰胺含量升高和RCM诱导的细胞损伤，而D609则不能，提示其可能与神经酰胺从头合成有关。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，导致细胞凋亡。在RCM肾病模型小鼠体内观察了伏马菌素Bl的保护作用。此外，前列环素类似物beraprost诱导内源性cAMP升高，有效预防造影剂肾病，其中涉及a激酶/PI 3激酶/Akt的激活以及CREB磷酸化。这些发现表明神经酰胺合成抑制剂或贝拉前列素可能对预防造影剂肾毒性有潜在的作用。

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.