Ceramide-induced apoptosis in renal tubular cells: a role of mitochondria and sphingosine-1-phoshate.
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.
Department of Pediatrics, Public Central Hospital of Matto Ishikawa, 3-8 Kuramitsu, Hakusan, Ishikawa 924-8588, Japan. nueda@mattohp.com.
Norishi
N
Ueda
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002518:Ceramides / Q000633:toxicity*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D002518:Ceramides; D008246:Lysophospholipids; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C060506:sphingosine 1-phosphate; D020928:Mitogen-Activated Protein Kinases; D013110:Sphingosine