Acute kidney injury (AKI) is a common cause of hospital-related mortality; therefore, strategies to either prevent or treat this complication are of great interest. In this issue of the JCI, Inoue, Abe, and colleagues have uncovered a targetable neuroimmunomodulatory mechanism that protects mice from ischemia-reperfusion injury (IRI) and subsequent AKI. Specifically, the authors demonstrate that vagus nerve stimulation (VNS) activates the cholinergic antiinflammatory pathway (CAP), resulting in activation of antiinflammatory effects via α7 nicotinic acetylcholine receptor-expressing splenic macrophages. Together, the results of this study have potential clinical implications in the prevention of AKI in at-risk individuals.