The metabolic regulator pregnane X receptor (PXR; encoded by Nr1i2) is dysregulated in several diseases, including chronic kidney disease (CKD), and is the focus of a new acute kidney injury (AKI) study by Yue Zhang, Zhanjun Jia, Aihua Zhang and colleagues. “Metabolic defects in kidney tubular cells contribute to the pathogenesis of AKI and we wanted to examine the role of PXR in this process,” explains Yue Zhang.

PXR was reduced in kidney biopsy samples of patients with AKI compared with healthy kidneys, and the intensity of PXR staining correlated negatively with blood urea nitrogen (BUN) and serum creatinine (sCr) levels. PXR expression also decreased in a time-dependent manner in the kidneys of mice with cisplatin-induced AKI.

In rats exposed to cisplatin, loss of PXR (Nr1i2−/−) aggravated tubular injury and significantly increased levels of BUN and sCr compared with wild-type controls; swollen mitochondria and disrupted cristae were also more abundant in the kidneys of Nr1i2−/− rats. These effects were accompanied by reduced expression of mitophagy-related genes and defective mitochondrial fatty acid oxidation. Inhibiting mitochondrial stress improved cisplatin-induced AKI in both wild-type and Nr1i2−/− rats. Kidney proteomics showed that PXR deletion significantly reduced the expression of aldo-keto reductase family 1 member B7 (AKR1B7), which was validated as a transcriptional target of PXR.

In contrast to PXR loss, administration of the PXR agonist pregnenolone-16α-carbonitrile (PCN) was renoprotective in murine models of cisplatin-induced AKI, but only in animals with intact PXR. In wild-type mice, in vivo overexpression of PXR or AKR1B7 induced by plasmid injection also protected animals against cisplatin-induced AKI and restored mitochondrial function.

“We are working on the generation of new PXR agonists, which might have therapeutic potential in AKI,” remarks Jia. “We also plan to study the potential role of PXR in the pathogenesis of CKD and in AKI to CKD transition,” adds Aihua Zhang.