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Abstract: TH-OR084

MAD2B Contributes to Parietal Epithelial Cell Activation and Crescentic Glomerulonephritis via Skp2

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Ye, Chen, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HUBEI, China
  • Su, Hua, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HUBEI, China
  • Zhang, Chun, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HUBEI, China
Background

Mitotic spindle assembly checkpoint protein 2 (MAD2B), a well-defined anaphase-promoting complex/cyclosome (APC/C) inhibitor and a small subunit of DNA polymerase zeta, is critical for mitotic control and DNA repair. Previously, we reported that upregulation of MAD2B is involved in several renal diseases. However, the pathological role of MAD2B in crescentic glomerulonephritis (CGN) has not been fully elucidated.

Methods

The objects of this study included patients with CGN, anti-glomerular basement membrane (anti-GBM) rats and in vitro cultured mouse PECs. In vivo, the anti-GBM model was established by intravenous injection of sheep anti-GBM serum and intraperitoneal administration of recombinant human TNF receptor-Ig fusion protein (TNFR:Fc) and prednisolone (PNS) were adopted to slow down crescent formation. In vitro gene silence of MAD2B and Skp2 were carried out by small interfering (si) RNA.

Results

In the present study, we found an obvious MAD2B enhancement in glomeruli of CGN patients and anti-GBM rats, which mainly originated from PECs. Consistently, MAD2B was increased in tumor necrosis factor-α (TNF-α)-treated PECs in vitro, accompanied by cell activation, proliferation and extracellular matrix accumulation. Importantly, knocking down MAD2B with siRNA dramatically attenuated PECs activation. Furthermore, we found that the expression of Skp2, an APC/C-CDH1 substrate, was increased in glomeruli of anti-GBM rats and TNF-α-induced PECs, which could be suppressed by MAD2B depletion. Also, genetic deletion of Skp2 inhibited TNF-α-induced PECs activation. Lastly, the administration of TNFR:Fc and PNS in anti-GBM rats reversed MAD2B and Skp2 accumulation, PEC activation, and subsequent crescent formation.

Conclusion

Our data suggests a pivotal role of MAD2B in the pathogenesis of glomerular PEC activation, proliferation and crescent formation by inducing Skp2 expression. MAD2B-Skp2 axis may be a promising potential target for glomerular crescent formation interventions.

Funding

  • Government Support - Non-U.S.