HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury
Zong-Jie Fu,
Zhi-Yu Wang,
Lian Xu,
Xiao-Hui Chen,
Xiang-Xiao Li,
Wei-Tang Liao,
Hong-Kun Ma,
Meng-Di Jiang,
Ting-Ting Xu,
Jing Xu,
Yan Shen,
Bei Song,
Ping-Jin Gao,
Wei-Qing Han,
Wen Zhang
Affiliations
Zong-Jie Fu
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai China, 200032, PR China
Zhi-Yu Wang
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Lian Xu
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Xiao-Hui Chen
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Xiang-Xiao Li
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Wei-Tang Liao
Research Center for Experimental Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Hong-Kun Ma
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Meng-Di Jiang
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Ting-Ting Xu
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Jing Xu
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Yan Shen
Research Center for Experimental Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Bei Song
Department of General Practice, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Ping-Jin Gao
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China
Wei-Qing Han
Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Ruijin Hospital, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Corresponding author. Department of Cardiovascular Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
Wen Zhang
Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China; Corresponding author. Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, PR China.
In the present study, we hypothesized that hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy plays a protective role in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Mitophagy was evaluated by measuring the changes of mitophagy flux, mitochondria DNA copy number, and the changes of mitophagy-related proteins including translocase of outer mitochondrial membrane 20 (TOMM20), cytochrome c oxidase IV (COX IV), microtubule-associated protein 1 light chain 3B (LC3B), and mitochondria adaptor nucleoporin p62 in HK2 cells, a human tubular cell line. Results show that HIF-1α knockout significantly attenuated hypoxia/reoxygenation (H/R)-induced mitophagy, aggravated H/R-induced apoptosis, and increased the production of reactive oxygen species (ROS). Similarly, H/R induced significantly increase in Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream regulator of HIF-1α. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1α knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1α knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1αflox/flox; cadherin-16-cre mice in which tubular HIF-1α was specifically knockout. It was found that tubular HIF-1α knockout significantly inhibited I/R-induced mitophagy, and aggravated I/R-induced tubular apoptosis and kidney damage. In contrast, adenovirus-mediated BNIP3 overexpression significantly reversed the decreased mitophagy, and prevented enhanced kidney damage in tubular HIF-1α knockout mice with I/R injury. In summary, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage.
