CONICET | Buscador de Institutos y Recursos Humanos

Death of photoreceptors is a leitmotif of retinal degenerations leading to blindness and identifying mediators that promote their survival might provide new therapeutical targets. Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator that regulates proliferation, survival, migration and inflammation in many cell types. S1P is synthesized by sphingosine kinase 1 (SphK1) and S1P might as an intracellular messenger or be released to activate a family of five G-protein coupled S1P membrane receptors (S1PRs). S1P roles in the retina are still poorly understood. We have shown that S1P promotes proliferation and differentiation in photoreceptors and rescues them from oxidative stress-induced apoptosis. Here we have explored the molecular pathways involved in S1P effects and whether it participates in neuro-glia crosstalk. S1P addition to pure neuronal cultures obtained from rat retinas led to a rapid increase in P-ERK levels in photoreceptors compared to controls. Pretreatment of these cultures with an inhibitor of the ERK/MAPK pathway abrogated S1P protection of photoreceptors from H2O2 induced oxidative stress. RT-PCR analysis evidenced the expression of S1P2 and S1P3 in neurons, whereas the presence of S1P3 in photoreceptors was determined by immunocytochemistry. Treatment of these cultures with a S1P3 antagonist blocked S1P protection from oxidative damage. Since Muller glial cells protect photoreceptors in co-culture from oxidative stress, we evaluated whether S1P might be one of the signals released by glial cells to promote this protection. Inhibiting S1P synthesis decreased glial protection of photoreceptors from oxidative stress-induced apoptosis. These results suggest that S1P activates the S1P3 and subsequently the ERK/MAPK pathway to promote photoreceptor survival. They also imply that glial cells release S1P to exert its protective effects on photoreceptors.