Research ArticleKidney Disease

Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI

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Science Translational Medicine  13 May 2020:
Vol. 12, Issue 543, eaay7591
DOI: 10.1126/scitranslmed.aay7591

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A nuclear option for acute kidney injury

Acute kidney injury is a life-threatening health problem with many potential causes such as hypoxic injury, toxins, and sepsis. Patients can recover with supportive care, but they may have long-lasting kidney damage that increases the risk of chronic kidney disease, and there is no specific targeted treatment. Yu et al. discovered that nuclear receptor PXR is down-regulated in the setting of acute kidney injury, which contributes to the impairment of mitochondrial function. Conversely, interventions that restored PXR function in mouse models of acute kidney injury were effective at protecting the kidneys, suggesting the potential for a therapeutic approach targeting PXR.

Abstract

Acute kidney injury (AKI) is a worldwide public health problem with no specific and satisfactory therapies in clinic. The nuclear pregnane X receptor (PXR) is involved in the progression of multiple diseases, including metabolic diseases, atherosclerosis, hypertension, liver injury, etc. However, its role in kidney injury remains to be understood. In this study, we have investigated the role of PXR in AKI and underlying mechanism(s) involved in its function. PXR was robustly down-regulated and negatively correlated with renal dysfunction in human and animal kidneys with AKI. Silencing PXR in rats enhanced cisplatin-induced AKI and induced severe mitochondrial abnormalities, whereas activating PXR protected against AKI. Using luciferase reporter assays, genomic manipulation, and proteomics data analysis on the kidneys of PXR−/− rats, we determined that PXR targeted Aldo-keto reductase family 1, member B7 (AKR1B7) to improve mitochondrial function, thereby ameliorating AKI. We confirmed the protective role of PXR against kidney injury using genomic and pharmacologic approaches in an ischemia/reperfusion model of AKI. These findings demonstrate that disabling the PXR/AKR1B7/mitochondrial metabolism axis is an important factor that can contribute to AKI, whereas reestablishing this axis can be useful for treating AKI.

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