Mulay Shrikant R, Romoli Simone, Desai Jyaysi, Honarpisheh Mohammad Mohsen, Kumar Santhosh V, Anders Hans-Joachim, Thomasova Dana
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Division of Nephrology, Medizinische Klinik und Poliklinik IV, University Hospital of Ludwig-Maximilians-University, Munich, Germany.
Am J Pathol. 2016 Jun;186(6):1442-53. doi: 10.1016/j.ajpath.2016.01.017. Epub 2016 Apr 18.
Rapidly progressive glomerulonephritis is characterized by glomerular necroinflammation and crescent formation. Its treatment includes unspecific and toxic agents; therefore, the identification of novel therapeutic targets is required. The E3-ubiquitin ligase murine double minute (MDM)-2 is a nonredundant element of NF-κB signaling and the negative regulator of tumor suppressor gene TP53-mediated cell cycle arrest and cell death. We hypothesized that the MDM2 would drive crescentic glomerulonephritis by NF-κB-dependent glomerular inflammation and by p53-dependent parietal epithelial cell hyperproliferation. Indeed, the pre-emptive MDM2 blockade by nutlin-3a ameliorated all aspects of crescentic glomerulonephritis. MDM2 inhibition had identical protective effects in Trp53-deficient mice, with the exception of crescent formation, which was not influenced by nutlin-3a treatment. In vitro experiments confirmed the contribution of MDM2 for induction of NF-κB-dependent cytokines in murine glomerular endothelial cells and for p53-dependent parietal epithelial cell proliferation. To evaluate MDM2 blockade as a potential therapeutic intervention in rapidly progressive glomerulonephritis, we treated mice with established glomerulonephritis with nutlin-3a. Delayed onset of nutlin-3a treatment was equally protective as the pre-emptive treatment in abrogating crescentic glomerulonephritis. Together, the pathogenic effects of MDM2 are twofold, that is, p53-independent NF-κB activation increasing intraglomerular inflammation and p53-dependent parietal epithelial cell hyperplasia and crescent formation. We therefore propose MDM2 blockade as a potential novel therapeutic strategy in rapidly progressive glomerulonephritis.
快速进展性肾小球肾炎的特征是肾小球坏死性炎症和新月体形成。其治疗包括使用非特异性和有毒药物；因此，需要确定新的治疗靶点。E3泛素连接酶小鼠双微体（MDM）-2是NF-κB信号通路的一个非冗余元件，也是肿瘤抑制基因TP53介导的细胞周期阻滞和细胞死亡的负调节因子。我们假设MDM2会通过NF-κB依赖的肾小球炎症和p53依赖的壁层上皮细胞过度增殖来驱动新月体性肾小球肾炎。事实上，nutlin-3a对MDM2的预先阻断改善了新月体性肾小球肾炎的各个方面。MDM2抑制在Trp53基因缺陷小鼠中具有相同的保护作用，但新月体形成除外，nutlin-3a治疗对其没有影响。体外实验证实了MDM2在诱导小鼠肾小球内皮细胞中NF-κB依赖的细胞因子以及p53依赖的壁层上皮细胞增殖中的作用。为了评估MDM2阻断作为快速进展性肾小球肾炎潜在治疗干预措施的效果，我们用nutlin-3a治疗患有已确立肾小球肾炎的小鼠。在消除新月体性肾小球肾炎方面，延迟开始使用nutlin-3a治疗与预先治疗具有同样的保护作用。总之，MDM2的致病作用有两方面，即p53非依赖的NF-κB激活增加肾小球内炎症，以及p53依赖的壁层上皮细胞增生和新月体形成。因此，我们提出MDM2阻断作为快速进展性肾小球肾炎潜在的新治疗策略。
