Renal Division, Medizinische Klinik and Poliklinik IV, Universität München, Germany.
Kidney Int. 2012 Jun;81(12):1199-211. doi: 10.1038/ki.2011.482. Epub 2012 Feb 1.
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.
鼠双微体 2（MDM-2）是一种 E3 泛素连接酶，通过降解细胞周期调控因子 p53 促进癌细胞的存活和生长。小分子顺式咪唑啉类 nutlin 类似物拮抗 MDM2 目前正在进行癌症治疗研究。为了测试 MDM2 是否也促进再生细胞生长，我们研究了 nutlin-3a 在缺血性急性肾损伤（AKI）后小管细胞修复中的作用。在野生型小鼠中，nutlin-3a 在 p53 依赖性方式下损害缺血后 AKI 期间的小管细胞再生；然而，MDM2 阻断也通过抑制缺血后早期的无菌炎症来防止小管坏死。这一效应也发生在 p53 敲除小鼠中，表明 MDM2 在 AKI 中具有第二种促炎的、p53 非依赖性作用。体外实验证实，当 Toll 样受体受到刺激时，NFκB 与细胞因子启动子结合位点的结合增强，MDM2 通过诱导 NFκB 依赖性细胞因子的 mRNA 表达和分泌，从而诱导 NFκB 依赖性细胞因子的表达和分泌。因此，MDM2 在 AKI 期间连接炎症和上皮愈合。在考虑 MDM2 抑制治疗时，需要考虑这些额外的生物学功能。
