MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation
MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation
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MAD2B 通过诱导细胞周期蛋白 B1 和 Skp2 积累导致糖尿病肾病足细胞损伤
DOI：
10.1152/ajprenal.00409.2014
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发表时间：
2015-04-01
影响因子：
4.2
通讯作者：
Zhang, Chun
中科院分区：
文献类型：
--
作者：
Su, Hua;Wan, Qiang;Zhang, Chun
有充分的证据表明，有丝分裂阻滞缺陷（MAD）2B可以通过钙粘蛋白（Cdh）1抑制后期促进复合物/细胞周期体（APC/C），从而破坏有效的有丝分裂纺锤体检查点控制。已经观察到足细胞在被迫绕过细胞周期检查点时快速分离和死亡。然而，细胞周期调节因子MAD 2B在糖尿病肾病（DN）足细胞损伤中的作用尚不清楚。在本研究中，我们研究了MAD 2B在DN患者、动物模型和体外足细胞培养中的发病机制中的意义。通过Western blot和免疫组化分析，我们发现在体内和体外高糖环境下MAD 2B表达明显上调，而Cdh 1则受到抑制。通过质粒DNA转染在足细胞中过表达MAD 2B抑制Cdh 1的表达，并触发细胞周期蛋白B1和S期激酶相关蛋白（Skp）2的积累，这两个关键分子参与细胞周期调控，以及随后的足细胞损伤。相比之下，MAD 2B缺失缓解了高葡萄糖诱导的Cdh 1减少以及细胞周期蛋白B1和Skp 2的升高，从而挽救了足细胞免受损伤。总之，我们的数据表明，MAD 2B可能通过调节Cdh 1，细胞周期蛋白B1和Skp 2的表达在高糖介导的DN足细胞损伤中发挥重要作用。
It is well documented that mitotic arrest deficiency (MAD) 2B can inhibit the anaphase-promoting complex/cyclosome (APC/C) via cadherin (Cdh) 1 and, consequently, can destroy the effective mitotic spindle checkpoint control. Podocytes have been observed to rapidly detach and die when being forced to bypass cell cycle checkpoints. However, the role of MAD2B, a cell cycle regulator, in podocyte impairment of diabetic nephropathy (DN) is unclear. In the present study, we investigated the significance of MAD2B in the pathogenesis of DN in patients, an animal model, and in vitro podocyte cultures. By Western blot and immunohistochemistry analyses, we found that MAD2B was evidently upregulated under high glucose milieu in vivo and in vitro, whereas Cdh1 was inhibited with high glucose exposure. Overexpression of MAD2B in podocytes by plasmid DNA transfection suppressed expression of Cdh1 and triggered the accumulation of cyclin B1 and S phase kinase-associated protein (Skp) 2, two key molecules involving in cell cycle regulation, and the subsequent podocyte insult. In contrast, MAD2B deletion alleviated the high glucose-induced reduction of Cdh1 as well as the elevation of cyclin B1 and Skp2, which rescued the podocyte from damage. Taken together, our data demonstrate that MAD2B may play an important role in high glucose-mediated podocyte injury of DN via modulation of Cdh1, cyclin B1, and Skp2 expression.