MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice.

Shrikant R Mulay, Dana Thomasova, Mi Ryu, Hans-Joachim Anders

Renal Division, Medizinische Klinik and Poliklinik IV, Universität München, Germany.

Kidney international 2012 Jun

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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.

Citation

Shrikant R Mulay, Dana Thomasova, Mi Ryu, Hans-Joachim Anders. MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice. Kidney international. 2012 Jun;81(12):1199-211