nutlin-3a and Reperfusion-Injury

Murine double minute (MDM)-2, an E3 ubiquitin ligase, promotes cancer cell survival and growth, by degrading the cell cycle regulator p53. Antagonism of MDM2 by the small-molecule cis-imidazoline nutlin analogs is under current study for cancer therapy. To test whether MDM2 also promotes regenerative cell growth, we determined the effects of nutlin-3a on tubule cell healing during postischemic acute kidney injury (AKI). Treatment with nutlin-3a impaired tubular cell regeneration during postischemic AKI in wild-type mice in a p53-dependent manner; however, MDM2 blockade also prevented tubular necrosis by suppressing sterile inflammation during the early postischemic phase. This effect also occurred in p53 knockout mice, indicating a second, proinflammatory, p53-independent role for MDM2 in AKI. In vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NFκB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NFκB to cytokine promoter-binding sites. Thus, MDM2 links inflammation and epithelial healing during AKI. These additional biological functions need to be regarded when considering MDM2 inhibition therapy.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Cells, Cultured; Cytokines; Disease Models, Animal; Gene Expression Regulation; Imidazoles; Inflammation; Inflammation Mediators; Injections, Intraperitoneal; Kidney Tubules; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; NF-kappa B; Piperazines; Proto-Oncogene Proteins c-mdm2; Regeneration; Reperfusion Injury; RNA, Messenger; Time Factors; Tumor Suppressor Protein p53; Wound Healing