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

Redox Biology (Sep 2020)

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.

Journal volume & issue: Vol. 36
p. 101671

Abstract

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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.

Published in Redox Biology

ISSN: 2213-2317 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General); Science: Biology (General)
Website: http://www.journals.elsevier.com/redox-biology/

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