Activation of BNIP3-mediated mitophagy protects against renal ischemia\u2013reperfusion injury

Chengyuan Tang,Juan Cai,Zhiwen Liu,Xiao-Ming Yin,Zheng Dong,Lijun Yin,Hailong Han,Yu Liu,Liyu He,Yuxue Liu,Zhuohua Zhang,Guochun Chen

doi:10.1038/s41419-019-1899-0

Abstract

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.

Highlights

Acute kidney injury (AKI) is a clinical syndrome of abrupt loss of renal functions that is pathologically featured by sublethal and lethal injury of renal tubules
We have investigated the role of BCL2-interacting protein 3 (BNIP3) in the development of ischemic AKI by using cultured renal proximal tubular cells (RPTCs) subjected to oxygen-glucose deprivation and reoxygenation (OGD-R) and a mouse model of renal IR injury as model systems
We first evaluated the expression of BNIP3 in Boston University mouse proximal tubule (BUMPT) cells that were subjected to OGD-R to mimic in vivo IR

Summary

Introduction

Acute kidney injury (AKI) is a clinical syndrome of abrupt loss of renal functions that is pathologically featured by sublethal and lethal injury of renal tubules. The clinical risk factors for AKI mainly include renal ischemia–reperfusion (IR), nephrotoxins, and sepsis. AKI has poor short- and long-term outcome. Besides its high short-term mortality, AKI has been recently recognized as an important risk factor for the development of chronic kidney disease (CKD)[1,2]. Mitophagy is a specific form of autophagy that selectively degrades mitochondria. As a critical component of mitochondrial quality control, mitophagy targets damaged or dysfunctional mitochondria for prompt elimination, thereby preventing excessive reactive oxygen species (ROS) production, and release of mitochondrial pro-apoptotic factors and damage-associated molecular patterns (DAMPs) that may promote pathological inflammatory responses[6,14]. Mitophagy requires a coordinative induction of autophagy and mitochondrial priming for autophagic recognition. Two mitochondrial priming mechanisms have been proposed, which rely on PTEN-induced kinase 1 (PINK1)parkin RBR E3 ubiquitin protein ligase (PARK2) pathway

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Conclusion