Sphingosine-1-phosphate is a lipid mediator that has been implicated in protection from acute kidney injury (AKI) by activation of the sphingosine-1-phosphate 1 receptor (S1P1R). The research team of H. Thomas Lee demonstrates that mice with induced deletion of S1P1R on endothelial cells experience increased ischemia-induced AKI. These findings have important translational implications. Indeed, S1P1R agonists have been used for the treatment of patients suffering from autoimmune encephalitis. Endothelial S1P1R signaling could be targeted for AKI prevention in surgical patients.