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

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.

• Authors: Xiaowen Yu, Man Xu, Xia Meng, Shumin Li, Qianqi Liu, Mi Bai, Ran You, Songming Huang, Li Yang, Yue Zhang, Zhanjun Jia, Aihua Zhang
• Journal: Science translational medicine (Sci Transl Med) Vol. 12 Issue 543 (05 13 2020) ISSN: 1946-6242 [Electronic] United States
• PMID: 32404507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Pregnane X Receptor
• Receptors, Cytoplasmic and Nuclear
• Akr1b7 protein, rat
• Aldehyde Reductase

Topics

• Acute Kidney Injury
• Aldehyde Reductase
• Animals
• Kidney (metabolism)
• Mitochondria
• Pregnane X Receptor (metabolism)
• Rats
• Receptors, Cytoplasmic and Nuclear (metabolism)