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

Xie, Yuxin1,2; Liu, Bohao1,2; Pan, Jian1,2; Liu, Jiamiao2; Li, Xiaozhou1,2; Li, Huiling3; Qiu, Shuangfa1,2; Xiang, Xudong1,2; Zheng, Peiling6; Chen, Junxiang4; Yuan, Yunchang5; Dong, Zheng4,7,8; Zhang, Dongshan1,2,4

2021-03-05

10.1016/j.omtn.2020.09.028

Molecular Therapy-Nucleic Acids   影响因子和分区

2162-2531

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.

SCI

英语

其他

National Natural Science Foundation of China[81870475,81570646,81770951] ; Excellent Youth Foundation of Hu'nan Scientific Committee[2017JJ1035] ; Changsha Science and Technology Bureau["kq1901115","kq2001039","kq1907144"]

Research & Experimental Medicine

Medicine, Research & Experimental

WOS:000631863200006

CELL PRESS

Web of Science

1.Cent South Univ, Xiangya Hosp 2, Dept Emergency Med, Changsha, Hunan, Peoples R China
2.Cent South Univ, Xiangya Hosp 2, Emergency Med & Difficult Dis Inst, Changsha, Hunan, Peoples R China
3.Cent South Univ, Xiangya Hosp 2, Dept Ophthalmol, Changsha, Hunan, Peoples R China
4.Cent South Univ, Xiangya Hosp 2, Dept Nephrol, Changsha, Hunan, Peoples R China
5.Cent South Univ, Xiangya Hosp 2, Dept Chest Surg, Changsha, Hunan, Peoples R China
6.Southern Univ Sci & Technol, Affiliated Hosp 1, Jinan Univ, Dept Endocrinol,Shenzhen Peoples Hosp,Clin Med Cl, Shenzhen, Peoples R China
7.Georgia Regents Univ, Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA USA
8.Charlie Norwood VA Med Ctr, Augusta, GA USA

Xie, Yuxin,Liu, Bohao,Pan, Jian,et al. MBD2 Mediates Septic AKI through Activation of PKC eta/p38MAPK and the ERK1/2 Axis[J]. Molecular Therapy-Nucleic Acids,2021,23.

Xie, Yuxin.,Liu, Bohao.,Pan, Jian.,Liu, Jiamiao.,Li, Xiaozhou.,...&Zhang, Dongshan.(2021).MBD2 Mediates Septic AKI through Activation of PKC eta/p38MAPK and the ERK1/2 Axis.Molecular Therapy-Nucleic Acids,23.

Xie, Yuxin,et al."MBD2 Mediates Septic AKI through Activation of PKC eta/p38MAPK and the ERK1/2 Axis".Molecular Therapy-Nucleic Acids 23(2021).