Liu G, Kleine L, Nasrallah R, Hébert R L
Departments of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
Am J Physiol. 1999 Apr;276(4):F589-98. doi: 10.1152/ajprenal.1999.276.4.F589.
Recent reports suggest that inflammatory cytokines, growth factors, and vasoconstrictor peptides induce sphingomyelinase (SMase) activity. This results in the hydrolysis of sphingomyelin (SM) into ceramide, which is implicated in various cellular functions. Although ceramide regulates phospholipase D (PLD) activity, there is controversy about this relationship. Thus we investigated whether the effect of bradykinin (BK), a proinflammatory factor and vasodilator, was mediated by ceramide signal transduction and by PLD. In rabbit cortical collecting duct (RCCD) cells, BK increased SM levels and decreased ceramide levels in a time-dependent manner. Thus SMase activity was inhibited by BK. Also, the production of ceramide was regulated in a concentration-dependent manner. The BK-B1 antagonist [Lys-des-Arg9,Leu8]BK did not affect ceramide signal transduction but the BK-B2 antagonist (Hoe-140) blocked the effect of BK on SMase, suggesting that the BK-B2 receptor mediates BK-induced inhibition of ceramide generation. Our results show that exogenous SMase significantly hydrolyzed endogenous SM to form ceramide and weakly activated PLD. In contrast, BK induced a significant activation of PLD. However, additive effects of BK and ceramide on PLD activity were not observed. We concluded that in RCCD cells, the BK-induced second messengers ceramide and phosphatidic acid were generated by distinct signal transduction mechanisms, namely the SMase and PLD pathways.
最近的报告表明，炎性细胞因子、生长因子和血管收缩肽可诱导鞘磷脂酶（SMase）活性。这导致鞘磷脂（SM）水解为神经酰胺，而神经酰胺与多种细胞功能有关。尽管神经酰胺调节磷脂酶D（PLD）的活性，但关于这种关系仍存在争议。因此，我们研究了促炎因子和血管舒张剂缓激肽（BK）的作用是否由神经酰胺信号转导和PLD介导。在兔皮质集合管（RCCD）细胞中，BK以时间依赖性方式增加SM水平并降低神经酰胺水平。因此，BK抑制了SMase活性。此外，神经酰胺的产生受到浓度依赖性调节。BK-B1拮抗剂[Lys-des-Arg9，Leu8]BK不影响神经酰胺信号转导，但BK-B2拮抗剂（Hoe-140）阻断了BK对SMase的作用，表明BK-B2受体介导BK诱导的神经酰胺生成抑制。我们的结果表明，外源性SMase可显著水解内源性SM以形成神经酰胺，并微弱激活PLD。相反，BK诱导了PLD的显著激活。然而，未观察到BK和神经酰胺对PLD活性的叠加作用。我们得出结论，在RCCD细胞中，BK诱导的第二信使神经酰胺和磷脂酸是通过不同的信号转导机制产生的，即SMase和PLD途径。
