title: MAD2B contributes to podocyte injury of diabetic nephropathy via inducing cyclin B1 and Skp2 accumulation.
abstract: 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.
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Hua
authors: H
authors: Su
authors: Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China; and.
authors: Qiang
authors: Q
authors: Wan
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Xiu-Juan
authors: XJ
authors: Tian
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Fang-Fang
authors: FF
authors: He
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Pan
authors: P
authors: Gao
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Hui
authors: H
authors: Tang
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Chen
authors: C
authors: Ye
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Di
authors: D
authors: Fan
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Shan
authors: S
authors: Chen
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
authors: Yu-Mei
authors: YM
authors: Wang
authors: Department of Neurobiology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Xian-Fang
authors: XF
authors: Meng
authors: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; drzhangchun@hust.edu.cn.
authors: Chun
authors: C
authors: Zhang
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D000818:Animals; D064200:Cdh1 Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D064246:Mad2 Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000502:physiology; D050199:Podocytes / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D064246:Mad2 Proteins; D044786:S-Phase Kinase-Associated Proteins; D064173:Anaphase-Promoting Complex-Cyclosome
keywords: S phase kinase-associated protein 2; cyclin B1; diabetic nephropathy; mitotic arrest deficiency 2B; podocytes