Ueda Norishi
Department of Pediatrics, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-8588, Japan.
Int J Mol Sci. 2015 Mar 5;16(3):5076-124. doi: 10.3390/ijms16035076.
Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed.
神经酰胺在受到刺激时合成，并诱导肾小管细胞（RTCs）凋亡。1-磷酸鞘氨醇（S1P）发挥存活因子的作用。因此，神经酰胺/S1P的平衡决定了神经酰胺诱导的凋亡。线粒体通过改变线粒体外膜通透性（MOMP）在神经酰胺诱导的凋亡中起关键作用。神经酰胺增强促凋亡Bcl-2家族蛋白的寡聚化、神经酰胺通道，并减少线粒体外膜中的抗凋亡Bcl-2蛋白。这一过程改变MOMP，导致活性氧（ROS）生成、细胞色素C释放到细胞质中、半胱天冬酶激活以及凋亡。神经酰胺通过丝裂原活化蛋白激酶（MAPKs）依赖和非依赖途径调节凋亡。相反，MAPKs通过调节参与神经酰胺代谢的酶来改变神经酰胺的生成，影响神经酰胺诱导的凋亡。Bcl-2家族蛋白、ROS和许多信号通路之间的相互作用调节神经酰胺诱导的凋亡。生长因子通过调节参与神经酰胺代谢、S1P的酶以及包括MAPKs在内的信号通路来挽救神经酰胺诱导的凋亡。本文综述了支持神经酰胺在凋亡中作用的证据，并讨论了线粒体的作用，包括MOMP、Bcl-2家族蛋白、ROS和信号通路，以及这些因素在调节RTCs神经酰胺诱导凋亡中的相互作用。还讨论了神经酰胺和S1P之间的平衡作用以及生长因子预防神经酰胺诱导凋亡的策略。
