| First Author | Mulay SR | Year | 2012 |
| Journal | Kidney Int | Volume | 81 |
| Issue | 12 | Pages | 1199-211 |
| PubMed ID | 22297670 | Mgi Jnum | J:198187 |
| Mgi Id | MGI:5495631 | Doi | 10.1038/ki.2011.482 |
| Citation | Mulay SR, et al. (2012) MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice. Kidney Int 81(12):1199-211 |
| abstractText | 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 NFkappaB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NFkappaB 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. |
