Sphingosine: a mediator of acute renal tubular injury and subsequent cytoresistance.

Abstract

The goal of this study was to determine whether sphingosine and ceramide, second messengers derived from sphingolipid breakdown, alter kidney proximal tubular cell viability and their adaptive responses to further damage. Adult human kidney proximal tubular (HK-2) cells were cultured for 0-20 hr in the presence or absence of sphingosine, sphingosine metabolites (sphingosine 1-phosphate, dimethylsphingosine), or C2, C8, or C16 ceramide. Acute cell injury was assessed by vital dye exclusion and tetrazolium dye transport. Their subsequent impact on superimposed ATP depletion/Ca2+ ionophore-induced damage was also assessed. Sphingosine (210 ,LM), sphingosine 1-phosphate, dimethylsphingosine, and selected ceramides (C2 and C8, but not C16) each induced rapid, dose-dependent cytotoxicity. This occurred in the absence of DNA laddering or morphologic changes of apoptosis, suggesting a necrotic form of cell death. Prolonged exposure (20 hr) to subtoxic sphingosine doses (57.5 ,IM) induced substantial cytoresistance to superimposed ATP depletion/Ca2+ ionophore-mediated damage. Conversely, neither short-term sphingosine treatment (58.5 hr) nor 20-hr exposures to any of the above sphingosine/ceramide derivatives/metabolites or various free fatty acids reproduced this effect. Sphingosine-induced cytoresistance was dissociated from the extent ofcytosolic Ca2+ loading (indo-1 fluorescence), indicating a direct increase in cell resistance to attaclk We conclude that sphingosine can exert dual effects on proximal renal tubular viability: in high concentrations it induces cell necrosis, whereas in low doses it initiates a cytoresistant state. These results could be reproduced in human foreskin fibroblasts, suggesting broad-based relevance to the area of acute cell injury and repair.It has long been recognized that plasma membrane phospholipids play crucial roles in cell signaling events. While most attention has been focused on glycerophospholipids and their metabolic byproducts, in recent years an important role for membrane sphingolipids has begun to emerge (e.g., refs. 1-4). Exploration of this area has been stimulated by observations that ceramide and sphingosine, lipid derivatives of sphingomyelin, can exert profound effects on cellular homeostasis. As examples, ceramide can inhibit cellular proliferation, induce differentiation, inhibit protein trafficking/secretion, and trigger apoptotic cell death (1-4). That these effects are likely mediated by secondary phosphorylation events (5-7) and that selected cytokines/hormones activate sphingomyelinases suggest that a ceramide/sphingosine signaling pathway exists (8-11).A characteristic feature of acute toxic and ischemic renal tubular cell injury is partial degradation of membrane lipid constituents, leading to the accumulation of lipid by-products (12)(13)(14)(15)(16)(17). This suggests that the sphingomyelinase/ceramide/ sphingosine pathway could be involved in acute cell injury and repair. That ischemia and cytosolic Ca2+ loading may activate sphingomyelinase(s) (18,...

Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat

“…5,6 Although ceramides Although ceramide signaling pathways have been imare well known to cause cell death by inducing apoptosis, plicated in cell death, neither their role in hepatocellular they can also cause cell death by necrosis. [3][4][5]7 Based on these death nor the cellular mechanisms mediating ceramidedata, we generated the hypothesis that the ceramide signalinduced cell death are known. The mitochondrial meming pathway induces cell death in hepatocytes, either by causbrane permeability transition (MMPT) has been proing apoptosis or necrosis.…”

“…[3][4][5]7 Based on these death nor the cellular mechanisms mediating ceramidedata, we generated the hypothesis that the ceramide signalinduced cell death are known. The mitochondrial meming pathway induces cell death in hepatocytes, either by causbrane permeability transition (MMPT) has been proing apoptosis or necrosis.…”

UDP-GlcNAc2-epimerase regulates cell surface sialylation and ceramide-induced cell death in human malignant lymphoma

“…Ceramide is converted to sphingosine by the activity of ceramidase and is subsequently converted to sphingosine-1-phosphate by the activity of sphingosine kinase (20) at the cell surface or extracellular milieu (21). Sphingosine induces rapid, necrotic cell death (22). In the present study, cell surface sialylation appears to be closely associated with ceramide or sphingosineinduced cell death.…”

“…Stress signals produce ceramide (18,19), and ceramide is converted to sphingosine by the activity of ceramidase and subsequently converted to sphingosine-1-phosphate by the activity of sphingosine kinase (20) at the cell surface or extracellular milieu (21). Sphingosine induces a rapid necrotic cell death (22).…”

Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

“…S1P binds to receptors or acts as an intracellular second messenger to stimulate cell survival, inhibit cell apoptosis, inhibit cell adhesion and movement [42][43][44][45][46][47][48]. However, accumulation of cell membrane lipid by-products including sphingomyelin/ceramide/sphingosine pathway is involved in acute renal tubular cell injury [49]. FTY720, a sphingosine analog, is a potent immunomodulator that has been tested for prevention of rejection in kidney transplantation [50,51].…”