Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

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.

ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

“…The accumulation of triglycerides is consistent with enhanced lipid storage, but shed little light on the source of those lipids, since lipid accumulation in this case was best explained by small accumulations of many diverse lipid species, rather than unique accumulation of one or a few such species. The accumulation of ceramides was accompanied by upregulation of Sptlc1 , which encodes the rate-limiting enzyme in ceramide synthesis, and also by enhanced TUNEL staining indicative of cell death, known to be associated with elevated ceramides (Mather and Siskind, 2011; Ueda, 2015) (Figure S1). This finding suggests that ceramide synthesis is actively regulated by prolonged ER stress in the kidney—a finding which awaits mechanistic investigation.…”

“…Given that Atf6α -/- animals show evidence of cell death in the kidney (Figure S1B), one possibility is that unmitigated ER stress in the Atf6α -/- kidney damages the organ beyond repair through extensive apoptosis and/or necrosis. Indeed, one of the other notable features of our lipidomic analysis was the elevation of several species putatively identified as ceramides (Table 1), which are known mediators of cell death pathways and serve as biomarkers for renal injury (Mather and Siskind, 2011; Ueda, 2015). We also favor the kidney as the most probable primary site of TM-induced anorexia in Atf6α -/- mice in part because the liver—the other organ most clearly targeted by TM—while clearly adversely affected by ER stress in these animals—is so resilient to lipid accumulation and cell loss (Forbes and Newsome, 2016).…”

Ceranib‐2‐induced suicidal erythrocyte death

“…The sphingolipid ceramide has been shown to trigger apoptosis in a wide variety of cells . Ceramide induced cell death involves mitochondria . Ceramide may be hydrolyzed to sphingosine 1 phosphate by the action of acid ceramidase .…”

Nanoflow-Nanospray Mass Spectrometry Metabolomics Reveals Disruption of the Urinary Metabolite Profiles of HIV-Positive Patients on Combination Antiretroviral Therapy

“…However, a C17 sphinganine has been detected in human plasma as a biomarker of kidney cancer. 40 The role of sphingolipid bases in HIV infection is currently unknown, but sphingolipids and their metabolites can initiate cellular apoptosis 41 , regulate HIV viral entry into cells 42,43 and are associated with age-related changes in cholesterol/low density lipoprotein levels. 44 Concentrations of a tetrapeptide increased in patients on atazanavir, possibly as a result of TDF and reduced proximal tubular function and reduced re-uptake of low molecular weight proteins.…”