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

Abstract

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 (PKCη), 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 PKCη via suppression of promoter methylation. Furthermore, PKCη 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 PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.

Loss of MBD2 ameliorates LPS‐induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis

“…51 MBD2 was reported to activate 10 to 11 translocation 1 (TET1) and microRNA 200s (miR-200s) expression and induce apoptosis in lung adenocarcinoma cells, 52 and further studies have revealed that MBD2 promotes apoptosis of retinal cells 13 and renal tubular cells. 12,39,53 In the present study, we have found that loss of MBD2 protected AECs from LPS-induced apoptosis, to the best of our knowledge this is the first report that MBD2 could mediate apoptosis in AECs and lungs, which might provide a novel drug intervention target in future.…”

“…38 Recently, Yuxin Xie et al reported that MBD2 promoted apoptosis of renal tubular cells, and MTF1 is one of the MBD2 targets involved. 39 In the present study, we have found that LPS treatment induced the expression of MTF1 and ZnT1 both in vivo and in vitro. Inhibition of MBD2 reduced MTF1 and ZnT1 levels, while the overexpression of MBD2 increased expression of MTF1 and ZnT1.…”

Wogonin alleviates liver injury in sepsis through Nrf2‐mediated NF‐κB signalling suppression

“…Besides, we conducted H&E staining analysis of renal tissues to examine the histological malformation of renal tissue in CLP‐induced sepsis mice. According to the previous study, 19 the percentage of damaged renal tubules was used to assess the score of tissue damage. The criteria of tubular damage included loss of brush border, tubular dilation, cast formation, inflammatory cell infiltration and cell lysis.…”

“…The liver histopathological scores were calculated as previously reported 18 . The renal tissue damage scores were calculated as previously reported 19 . Briefly, the percentage of damaged renal tubules was used to assess the score of tissue damage: 0, no damage; 1, <25% damage; 2, 25%‐50% damage; 3, 51%‐75% damage; 4, >75% damage, and the criteria of tubular damage included loss of brush border, tubular dilation, cast formation, inflammatory cell infiltration and cell lysis.…”

The Programmed Cell Death of Macrophages, Endothelial Cells, and Tubular Epithelial Cells in Sepsis-AKI

“…Referring to the methylation in TECs during sepsis, Xie et al ( 197 ) highlighted the function of methyl-CpG binding domain protein 2 (MBD2). They showed that knockdown of MBD2 in Boston University mouse proximal tubule (BUMPT) cells or global knockout of MBD2 in mice could significantly improve survival.…”