Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI
- 13 May 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (543)
- https://doi.org/10.1126/scitranslmed.aay7591
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.Keywords
Funding Information
- National Natural Science Foundation of China (81830020)
- National Natural Science Foundation of China (81873599)
- National Natural Science Foundation of China (81700604)
This publication has 55 references indexed in Scilit:
- Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO)Kidney International, 2011
- Deficiency of PXR decreases atherosclerosis in apoE-deficient miceJournal of Lipid Research, 2011
- Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasisJournal of Lipid Research, 2011
- Nuclear receptors in renal diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2011
- Estimated Glomerular Filtration Rate Is a Poor Predictor of Concentration for a Broad Range of Uremic ToxinsClinical Journal of the American Society of Nephrology, 2011
- The Aldo-Keto Reductase Akr1b7 Gene Is a Common Transcriptional Target of Xenobiotic Receptors Pregnane X Receptor and Constitutive Androstane ReceptorMolecular Pharmacology, 2009
- Reduction of Renal Superoxide Dismutase in Progressive Diabetic NephropathyJournal of the American Society of Nephrology, 2009
- PXR induces CYP27A1 and regulates cholesterol metabolism in the intestineJournal of Lipid Research, 2007
- Regulation of CYP3A genes in the human respiratory tractChemico-Biological Interactions, 2005
- Substrate-utilization of the Human KidneyNature, 1966