DsbA-L interacts with VDAC1 in mitochondrion-mediated tubular cell apoptosis and contributes to the progression of acute kidney disease
Xiaozhou Li,
Jian Pan,
Huiling Li,
Guangdi Li,
Bohao Liu,
Xianming Tang,
Xiangfeng Liu,
Zhibiao He,
Zhenyu Peng,
Hongliang Zhang,
Luxiang Wang,
Yijian Li,
Xudong Xiang,
Xiangping Chai,
Yunchang Yuan,
Peilin Zheng,
Dongshan Zhang
Affiliations
Xiaozhou Li
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Jian Pan
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Huiling Li
Department of Ophthalmology, People's Republic of China
Guangdi Li
Department of Public Health, Central South University, Changsha, Hunan, People's Republic of China
Bohao Liu
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Xianming Tang
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Xiangfeng Liu
Department of General Surgery, Second Xiangya Hospital, People's Republic of China
Zhibiao He
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Zhenyu Peng
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Hongliang Zhang
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Luxiang Wang
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Yijian Li
Departmentof Urinary Surgery, People's Republic of China
Xudong Xiang
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Xiangping Chai
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China
Yunchang Yuan
Department of Chestsurgery, People's Republic of China
Peilin Zheng
Department of Endocrinology, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, People's Republic of China
Dongshan Zhang
Department of Emergency Medicine, People's Republic of China; Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China; Corresponding author at: Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, People's Republic of China.
Summary: Background: we demonstrated that disulfide-bond A oxidoreductase-like protein (DsbA-L) was involved in the progression of renal fibrosis. However, the precise function of DsbA-L in acute kidney injury (AKI), and the mechanisms involved, have yet to be elucidated. Methods: We illustrate the DsbA-L interacted with VDAC1 by co-IP (co-immunoprecipitation) in vitro and vivo, and found the interaction parts of them by mutation experiment. The above findings were verified by co-localization of them. In addition, we constructed the two model of PT-DsbA-L and VDAC1 KO mice to verify the function of DsbA-L and VDAC1 in models of VAN, CLP and I/R-induced AKI. Findings: The PT-DsbA-L-KO mice showed amelioration of I/R, VAN-, and CLP-induced AKI progression via the downregulation of VDAC1. Finally, we confirmed these changes in signal molecules by examining in HK-2 cells and kidney biopsies taken from patients with ischemic or acute interstitial nephritis (AIN)-induced AKI. Mechanistically, DsbA-L interacted with amino acids 9–13 and 22–27 of VDAC1 in the mitochondria of BUMPT cells to induce renal cell apoptosis and mitochondrial injury. Interpretation: This work suggested that DsbA-L, located in the proximal tubular cells, drives the progression of AKI, by directly upregulating the levels of VDAC1.Running Title: The role of DsbA-L in AKI Funding: National Natural Science Foundation of China, a grant from Key Project of Hunan provincial science and technology innovation, Department of Science and Technology of Hunan Province project of International Cooperation and Exchanges, Changsha Science and Technology Bureau project, Natural Science Foundation of Hunan Province, Fundamental Research Funds for the Central Universities of Central South University, Hunan Provincial Innovation Foundation For Postgraduate China Hunan Provincial Science and Technology Department.
