Pregnane X receptor increases urine concentration by upregulating hypothalamic arginine vasopressin expression

The pregnane X receptor (PXR) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. PXR is constitutively expressed in the hypothalamus and kidney, with its physiological function incompletely understood. In this study, we found that treatment with pregnenolone-16α-carbonitrile (PCN), an endogenous PXR ligand, significantly reduced urine volume and increased urine osmolarity in C57BL/6 mice. In contrast, PXR gene knockout (PXR^-/-) mice exhibited impaired urine-concentrating ability, leading to a polyuria phenotype. In addition, treatment of mice with PCN significantly upregulated, whereas PXR gene deficiency substantially reduced, arginine vasopressin (AVP) expression in the hypothalamus. Bioinformatic analysis showed that the mouse AVP gene promoter contains a putative PXR response element (PXRE). The luciferase reporter, ChIP, and electrophoretic mobility shift assays further revealed that PXR can bind to the PXRE, resulting in a significant increase in AVP gene transcription. Collectively, the present study demonstrates that hypothalamic PXR plays a critical role in regulating urine volume, and its activation enhances urine-concentrating capacity primarily by upregulating the expression of AVP in the hypothalamus.NEW & NOTEWORTHY Activation of PXR enhances urine concentration, whereas PXR deficiency diminishes this capacity. PXR is coexpressed with AVP in the hypothalamus, where it upregulates AVP transcription to promote renal water reabsorption. These findings reveal a novel role for PXR in regulating urinary concentration and propose its potential as a therapeutic target for water metabolism disorders, such as diabetes insipidus.