Acute kidney injury triggers activation of innate immune responses and of proapoptotic programs such as the p53 pathway. Mulay et al. examine the effects of blocking murine double minute-2 (mdm2), a negative regulator of p53, using a novel chemotherapeutic agent, nutlin-3a, in mouse ischemia-reperfusion injury. Their results indicate that mdm2 promotes renal regeneration by limiting p53-mediated apoptosis but also enhances early inflammation by facilitating DNA binding of nuclear factor-κB independently of p53.