MAD2B-mediated cell cycle reentry of podocytes is involved in the pathogenesis of FSGS.
Int J Biol Sci
; 17(15): 4396-4408, 2021.
Article
em En
| MEDLINE
| ID: mdl-34803506
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.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pironas
/
Glomerulosclerose Segmentar e Focal
/
Morfolinas
/
Podócitos
/
Proteínas Mad2
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article