Abstract
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.
Highlights
Ceramide, which belongs to sphingolipids, is recognized as a signaling molecule within the cell, sphingolipids have long been considered to be only structural components of the cell membranes
Mitochondria play a central role in the regulation of ceramide-induced apoptosis through an alteration of mitochondrial outer membrane permeability (MOMP) [4,5]
Mitochondria play a central role in the regulation of ceramide-induced apoptosis through its function, which is tightly regulated by Bcl-2 family proteins
Summary
Ceramide, which belongs to sphingolipids, is recognized as a signaling molecule within the cell, sphingolipids have long been considered to be only structural components of the cell membranes. Little is known about a role of ceramide in apoptosis of RTCs and the mechanism by which ceramide regulates the apoptotic processes in RTCs. This review aims to summarize evidence supporting a role of ceramide and the balance between ceramide and other sphingolipids, in particular S1P, in the regulation of apoptosis in RTCs. I will discuss a role of mitochondria, including alteration of MOMP, Bcl-2 family proteins and ROS generation, MAPKs, and other kinases as well as a crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. Strategy for preventing ceramide-induced apoptosis by growth factors, which can regulate ceramide metabolism and MAPKs, will be discussed
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