MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis

Our previous study demonstrated that the methyl-CpG-binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI are unknown. Herein, MBD2 was induced by lipopolysaccharide (LPS) in Boston University mouse proximal tubules (BUMPTs) and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) substantially improved the survival rate and attenuated both LPS and cecal ligation and puncture (CLP)-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of protein kinase C eta (PKCri), caused by LPS, is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, chromatin immunoprecipitation (ChIP) analysis indicates that MBD2 directly binds to promoter region CpG islands of PKC eta via suppression of promoter methylation. Furthermore, PKC eta siRNA improves the survival rate and attenuates LPS-induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2, which were further verified by PKC eta siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKC eta/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKC eta/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.

Automated summary

The study revealed that MBD2 plays a role in septic AKI by activating the PKC eta/p38MAPK and ERK1/2 axis. Inhibition of MBD2 or PKC eta can improve survival rate, alleviate AKI, and suppress inflammatory factor production.