Mitotic spindle assembly checkpoint protein 2 (MAD2B), a well-known anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase ζ, is critical for mitotic control and DNA repair. Previously, we detected a strong increase of MAD2B in the glomeruli from crescentic glomerulonephritis patients and anti-glomerular basement membrane (anti-GBM) rats, which predominantly originated from activated parietal epithelial cells (PECs). Consistently, in vitro MAD2B was increased in tumor necrosis factor-α (TNF-α)-treated PECs, along with cell activation and proliferation, as well as extracellular matrix accumulation, which could be reversed by MAD2B genetic depletion. Furthermore, we found that the expression of Skp2, an APC/CCDH1 substrate, was increased in the glomeruli of anti-GBM rats and TNF-α-stimulated PECs and could be suppressed by MAD2B depletion. Additionally, genetic deletion of Skp2 inhibited TNF-α-induced PEC activation and dysfunction. Finally, TNF-α blockade or glucocorticoid therapy administered to anti-GBM rats could ameliorate MAD2B and Skp2 accumulation, as well as weaken PEC activation. Collectively, our data suggest that MAD2B has a pivotal role in the pathogenesis of glomerular PEC activation and crescent formation through induction of Skp2 expression.

中文翻译：

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MAD2B通过Skp2促进顶叶上皮细胞活化和新月型肾小球肾炎。

有丝分裂纺锤体装配检查点蛋白2（MAD2B）是一种著名的后期促进复合物/环体（APC / C）抑制剂，是DNA聚合酶ζ的一个小亚基，对有丝分裂控制和DNA修复至关重要。以前，我们从新月型肾小球肾炎患者和抗肾小球基底膜（anti-GBM）大鼠的肾小球中检测到MAD2B的强烈增加，这些肾小球主要起源于活化的壁上皮细胞（PECs）。一致地，在肿瘤坏死因子-α（TNF-α）处理的PECs中，体外MAD2B增加，同时细胞活化和增殖以及细胞外基质积累也可能被MAD2B遗传耗竭所逆转。此外，我们发现APC / CCDH1底物Skp2的表达 抗GBM大鼠和TNF-α刺激的PECs的肾小球中的TNF-α升高，并且可以被MAD2B耗竭抑制。此外，Skp2的基因删除抑制了TNF-α诱导的PEC激活和功能障碍。最后，对抗GBM大鼠进行TNF-α阻断或糖皮质激素治疗可以改善MAD2B和Skp2的积累，并削弱PEC的激活。总体而言，我们的数据表明MAD2B通过诱导Skp2表达在肾小球PEC激活和新月形形成的发病机理中具有关键作用。