The MAD2B-APC/C-MDM2 axis mediates acute kidney injury by modulating p53

P53 is a master regulator modulating the progression of acute kidney injury (AKI). However, the mechanism underlying p53 regulation in AKI needs further investigation. Mitotic arrest deficient 2 like 2 (MAD2B) is a subunit of DNA polymerase zeta. Its role in AKI remains unclear. Here, we demonstrated that MAD2B acted as an endogenous suppressor of p53. MAD2B conditional knockout augmented the upregulation of p53 in kidneys suffering from cisplatin-induced AKI, therefore promoting the deterioration of renal function, G1 phase arrest and apoptosis of proximal tubular epithelial cells. Mechanistically, MAD2B deficiency activated the anaphase-promoting complex/cyclosome (APC/C), which is an inhibitor of the well-characterized p53-directed E3 ligase MDM2. The decreased MDM2 diminished the degradation of p53, resulting in the upregulation of p53. The APC/C antagonist proTAME ameliorated cisplatin-induced AKI and blocked MAD2B knockdown-induced p53 upregulation and reduced cell cycle arrest and apoptosis in tubular epithelial cells by upregulating MDM2. These results indicate that MAD2B is a novel target for inhibiting p53 and ameliorating AKI.

Automated summary

P53 is a master regulator involved in the progression of acute kidney injury (AKI). The role of Mitotic arrest deficient 2 like 2 (MAD2B) in AKI is unclear. This study demonstrates that MAD2B functions as an endogenous suppressor of p53. MAD2B knockout enhances the upregulation of p53 in cisplatin-induced AKI, leading to renal function deterioration, G1 phase arrest, and apoptosis of tubular epithelial cells. Mechanistically, MAD2B deficiency activates anaphase-promoting complex/cyclosome (APC/C), which inhibits the p53-directed E3 ligase MDM2. Decreased MDM2 results in the upregulation of p53.