Activation of BNIP3-mediated mitophagy protects against renal ischemia–reperfusion injury

• Published in: Cell death & disease Vol. 10; no. 9; pp. 677 - 15
• Main Authors: Tang, Chengyuan, Han, Hailong, Liu, Zhiwen, Liu, Yuxue, Yin, Lijun, Cai, Juan, He, Liyu, Liu, Yu, Chen, Guochun, Zhang, Zhuohua, Yin, Xiao-Ming, Dong, Zheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-09-2019; Springer Nature B.V
• Subjects: 13/2; 13/51; 13/89; 14/19; 14/28; 14/35; 631/80/39/2348; 64/110; 692/699/1585/4; 82/29; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Antibodies; Apoptosis; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; BNIP3 protein; Cell Biology; Cell Culture; Cell death; Cell survival; Epithelial cells; Glucose; Immunology; Inflammation; Ischemia; Kidney - metabolism; Kidney - pathology; Kidney Tubules - metabolism; Kidney Tubules - pathology; Kidneys; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondria - metabolism; Mitophagy; Mitophagy - genetics; Mitophagy - physiology; Quality control; Reactive oxygen species; Reactive Oxygen Species - metabolism; Renal function; Renal tubules; Reperfusion; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Signal Transduction - physiology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1899-0

Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia–reperfusion (IR)-induced injury in mice. Functionally, silencing
Bnip3
by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo,
Bnip3
knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that
Bnip3
knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.