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

放射造影剂(RCM)是药物所致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诱导肾小管上皮细胞的凋亡，其中涉及bcl2mRNA的减少以及随后caspase-9和caspase-3的激活。此外，RCM诱导的Bc l-2表达减少是通过减少磷酸化Akt和环磷酸腺苷(CAMP)反应元件结合蛋白(CREB)的磷酸化来实现的。各种RCM均使肾小管上皮细胞神经酰胺含量增加，其中神经酰胺含量的增加与细胞活力丧失密切相关。伏马菌素B1可逆转RCM引起的神经酰胺含量升高和细胞损伤，而D609则不能逆转，提示神经酰胺的从头合成作用。神经酰胺与RCM一样，降低了PACT，降低了Bcl2的表达，增强了caspase-9和caspase-3的活性，并导致细胞凋亡。在体内观察伏马菌素Bl对小鼠RCM肾病的保护作用。此外，前列环素类似物贝拉前列素可诱导内源性cAMP升高，从而有效地预防放射性造影剂肾病，这一过程涉及A激酶/PI3-激酶/Akt的激活和CREB的磷酸化，提示神经酰胺合成抑制剂或贝拉前列素可能有助于预防造影剂的肾毒性。

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.