Zhou et al. identify progranulin (PGRN) as a protective mediator that limits inflammation in murine models of acute kidney injury (AKI) and reduces its severity. Deficiency of PGRN was associated with increased inflammation and increased injury in ischemic and nephrotoxic models of AKI. Exogenous PGRN reduced AKI even when administered after AKI was established. Interference in NOD2 pathways is suggested as a possible mechanism for protection. PGRN-based therapeutics might have application in the treatment or prevention of AKI.