MAD2B contributes to parietal epithelial cell activation and crescentic glomerulonephritis via Skp2.
MAD2B contributes to parietal epithelial cell activation and crescentic glomerulonephritis via Skp2.
复制标题
DOI：
10.1152/ajprenal.00216.2020
复制
发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
C. Ye;W. Xiong;Chuntao Lei;Hui Tang;H. Su;F. Yi;Chun Zhang
中科院分区：
文献类型：
--
作者：
C. Ye;W. Xiong;Chuntao Lei;Hui Tang;H. Su;F. Yi;Chun Zhang
有丝分裂纺锤体组装检查点蛋白 2 (MAD2B) 是一种众所周知的后期促进复合物/环体 (APC/C) 抑制剂，也是 DNA 聚合酶 ζ 的一个小亚基，对于有丝分裂控制和 DNA 修复至关重要。此前，我们在新月体肾小球肾炎患者和抗肾小球基底膜（抗GBM）大鼠的肾小球中检测到MAD2B的强烈增加，其主要源自活化的壁上皮细胞（PEC）。一致地，体外肿瘤坏死因子-α (TNF-α) 处理的 PEC 中 MAD2B 增加，同时细胞活化和增殖以及细胞外基质积累，这可以通过 MAD2B 基因缺失来逆转。此外，我们发现 Skp2（一种 APC/CCDH1 底物）的表达在抗 GBM 大鼠的肾小球和 TNF-α 刺激的 PEC 中增加，并且可以通过清除 MAD2B 来抑制。此外，Skp2 的基因缺失抑制了 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 积累，并削弱 PEC 激活。总的来说，我们的数据表明 MAD2B 通过诱导 Skp2 表达在肾小球 PEC 激活和新月体形成的发病机制中发挥关键作用。
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.