MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS

Bao, Dian; Su, Hua; Lei, Chun-Tao; Tang, Hui; Ye, Chen; Xiong, Wei; He, Fang-Fang; Lin, Ji-Hong; Hammes, Hans-Peter; Zhang, Chun

doi:10.7150/ijbs.62238

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Int J Biol Sci 2021; 17(15):4396-4408. doi:10.7150/ijbs.62238 This issue Cite

Research Paper

MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS

Dian Bao^1#, Hua Su^1#, Chun-Tao Lei¹, Hui Tang¹, Chen Ye¹, Wei Xiong¹, Fang-Fang He¹, Ji-Hong Lin², Hans-Peter Hammes², Chun Zhang^1✉

1. Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2. 5th Medical Department, Medical Faculty Mannheim, University of Heidelberg, D-68167 Mannheim, Germany.
# These authors contributed equally to this work.

Citation:

Bao D, Su H, Lei CT, Tang H, Ye C, Xiong W, He FF, Lin JH, Hammes HP, Zhang C. MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. Int J Biol Sci 2021; 17(15):4396-4408. doi:10.7150/ijbs.62238. https://www.ijbs.com/v17p4396.htm

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Abstract

Rationale: Focal segmental glomerulosclerosis (FSGS) is characterized by the dysfunction of “post-mitotic” podocytes. The reentry of podocytes in the cell cycle will ultimately result in cell death. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of anaphase-promoting complex (APC)/cyclosome, precisely controls the metaphase to anaphase transition and ordered cell cycle progression. However, the role of MAD2B in FSGS podocyte injury remains unknown.

Methods: To explore MAD2B function in podocyte cell cycle reentry, we used conditional mutant mice lacking MAD2B selectively in podocytes in ADR-induced FSGS murine model. Additionally, KU-55933, a specific inhibitor of ataxia-telangiectasia mutated (ATM) was utilized in vivo and in vitro to explore the role of ATM in regulating MAD2B.

Results: The expression of MAD2B in podocytes was dramatically increased in patients with FSGS and ADR-treated mice along with podocyte cell cycle reentry. Podocyte-specific knockout of MAD2B effectively attenuated proteinuria, podocyte injury, and prevented the aberrant cell cycle reentry. By bioinformatics analysis we revealed that ATM kinase is a key upstream regulator of MAD2B. Furthermore, inhibition of ATM kinase abolished MAD2B-driven cell cycle reentry and alleviated podocyte impairment in FSGS murine model. In vitro studies by site-directed mutagenesis and immunoprecipitation we revealed ATM phosphorylated MAD2B and consequently hampered the ubiquitination of MAD2B in a phosphorylation-dependent manner.

Conclusions: ATM kinase-MAD2B axis importantly contributes to the cell cycle reentry of podocytes, which is a novel pathogenic mechanism of FSGS, and may shed light on the development of its therapeutic approaches.

Keywords: podocyte, FSGS, cell cycle reentry, MAD2B, ATM

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APA

Bao, D., Su, H., Lei, C.T., Tang, H., Ye, C., Xiong, W., He, F.F., Lin, J.H., Hammes, H.P., Zhang, C. (2021). MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. International Journal of Biological Sciences, 17(15), 4396-4408. https://doi.org/10.7150/ijbs.62238.

ACS

Bao, D.; Su, H.; Lei, C.T.; Tang, H.; Ye, C.; Xiong, W.; He, F.F.; Lin, J.H.; Hammes, H.P.; Zhang, C. MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. Int. J. Biol. Sci. 2021, 17 (15), 4396-4408. DOI: 10.7150/ijbs.62238.

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CSE

Bao D, Su H, Lei CT, Tang H, Ye C, Xiong W, He FF, Lin JH, Hammes HP, Zhang C. 2021. MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS. Int J Biol Sci. 17(15):4396-4408.

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