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

Yuxin Xie; Bohao Liu; Jian Pan; Jiamiao Liu; Xiaozhou Li; Huiling Li; Shuangfa Qiu; Xudong Xiang; Peiling Zheng; Junxiang Chen; Yunchang Yuan; Zheng Dong; Dongshan Zhang

Molecular Therapy: Nucleic Acids (Mar 2021)

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

Yuxin Xie,
Bohao Liu,
Jian Pan,
Jiamiao Liu,
Xiaozhou Li,
Huiling Li,
Shuangfa Qiu,
Xudong Xiang,
Peiling Zheng,
Junxiang Chen,
Yunchang Yuan,
Zheng Dong,
Dongshan Zhang

Affiliations

Yuxin Xie: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Bohao Liu: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Jian Pan: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Jiamiao Liu: Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Xiaozhou Li: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Huiling Li: Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Shuangfa Qiu: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Xudong Xiang: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Peiling Zheng: Department of Endocrinology, Shenzhen People’s Hospital, Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, People’s Republic of China
Junxiang Chen: Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Yunchang Yuan: Department of Chest Surgery, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China
Zheng Dong: Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University and Charlie Norwood VA Medical Center, Augusta, GA, USA
Dongshan Zhang: Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; Corresponding author: Dongshan Zhang, Department of Emergency Medicine, Emergency Medicine and Difficult Diseases Institute, Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People’s Republic of China.

Journal volume & issue: Vol. 23
pp. 76 – 88

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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