Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation

Ji Zhang,Gen Chen,Mengqin Wang,Yun Miao,Qingwen Li,Kailun Sun,Yanfeng Wang,Haiqiang Ni,Gaurav Katwal,Nianqiao Gong,Jiasi Zhang,Yuanyuan Zhao

doi:10.1038/s41420-021-00425-z

Abstract

Ischemia-reperfusion (IR) injury to the renal epithelia is associated with endoplasmic reticulum stress (ERS) and mitochondria dysfunction, which lead to oxidative stress-induced acute kidney injury (AKI). X-box binding protein 1 (XBP1), an ERS response protein, could play a prominent role in IR-induced AKI. In this study, we revealed that XBP1 and its downstream target HRD1 participated in the crosstalk between ERS and mitochondrial dysfunction via regulation of NRF2/HO-1-mediated reactive oxidative stress (ROS) signaling. Mice with reduced expression of XBP1 (heterozygous Xbp1±) were resistant to IR-induced AKI due to the enhanced expression of NRF2/HO-1 and diminished ROS in the kidney. Downregulation of XBP1 in renal epithelial cells resulted in reduced HRD1 expression and increased NRF2/HO-1 function, accompanied with enhanced antioxidant response. Furthermore, HRD1 served as an E3-ligase to facilitate the downregulation of NRF2 through ubiquitination-degradation pathway, and the QSLVPDI motif on NRF2 constituted an active site for its interaction with HRD1. Thus, our findings unveil an important physiological role for XBP1/HRD1 in modulating the antioxidant function of NRF2/HO-1 in the kidney under stress conditions. Molecular therapeutic approaches that target XBP1-HRD1-NRF2 pathway may represent potential effective means to treat renal IR injury.

Highlights

Renal ischemia-reperfusion injury (IRI) is one of the leading causes of acute kidney injury (AKI), which contributes to high morbidity and mortality rates worldwide[1,2]
X-boxbinding protein 1 (XBP1) is involved in the crosstalk between mitochondrial damage and endoplasmic reticulum stress (ERS) in renal IRI
The upregulation of XBP1s was prominent. These findings indicate the presence of crosstalk between mitochondrial damage and severe ERS in renal IRI, and the prominent high expression levels of XBP1s suggest that XBP1 may play a unique role in the crosstalk between mitochondrial damage and ERS during renal IRI

Summary

Introduction

Renal ischemia-reperfusion injury (IRI) is one of the leading causes of acute kidney injury (AKI), which contributes to high morbidity and mortality rates worldwide[1,2]. Several concomitant factors, such as reactive oxygen species (ROS) production, abnormal protein synthesis and increased cell death, can exacerbate the progression of renal IRI3–5. Cellular adaptation to ERS is achieved by the activation of unfolded protein response (UPR), which involves three principal ERS sensors, such as inositol-requiring enzyme 1α (IRE1α), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6)[16,17,18]. XBP1s plays a crucial role in cell survival and death by upregulating UPR-

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Conclusion