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- Title
MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice.
- Authors
Mulay, Shrikant R; Thomasova, Dana; Ryu, Mi; Anders, Hans-Joachim
- Abstract
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.
- Subjects
KIDNEY injuries; LABORATORY mice; UBIQUITIN ligases; CANCER cells; CELL cycle; IMMUNOREGULATION
- Publication
Kidney International, 2012, Vol 81, Issue 12, p1199
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.2011.482