MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice
MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice
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DOI：
10.1038/ki.2011.482
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发表时间：
2012-06-01
影响因子：
19.6
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Mulay, Shrikant R.;Thomasova, Dana;Anders, Hans-Joachim
小鼠双微体（MDM）-2，一种E3泛素连接酶，通过降解细胞周期调节因子p53促进癌细胞存活和生长。目前正在研究小分子顺式咪唑啉nutlin类似物对MDM 2的拮抗作用用于癌症治疗。为了测试MDM 2是否也促进再生细胞生长，我们确定了nutlin-3a在缺血后急性肾损伤（阿基）期间对肾小管细胞愈合的影响。在野生型小鼠中，用nutlin-3a治疗以p53依赖性方式损害了缺血后阿基期间的肾小管细胞再生;然而，MDM 2阻断还通过在缺血后早期抑制无菌炎症来防止肾小管坏死。这种效应也发生在p53基因敲除小鼠中，表明MDM 2在阿基中的第二种促炎性、p53非依赖性作用。体外实验证实，在Toll样受体刺激后，通过增强NF κ B B与细胞因子启动子结合位点的结合，需要MDM 2来诱导NF κ B依赖性细胞因子的mRNA表达和分泌。因此，MDM 2将阿基期间的炎症和上皮愈合联系起来。在考虑MDM 2抑制治疗时，需要考虑这些额外的生物学功能。
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 NF kappa B-dependent cytokines upon Toll-like receptor stimulation by enhanced binding of NF kappa B 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.