Pregnane X receptor mitigates aristolochic acid-induced acute kidney injury via p53 ubiquitination.

Abstract

Aristolochic acid (AA), commonly used in Chinese herbal medicine to treat various diseases, can cause acute kidney injury (AKI). The pregnane X receptor (PXR), a nuclear receptor, is involved in drug metabolism, carcinogenesis, inflammation, apoptosis, oxidative stress and energy metabolism. Here, we demonstrate that PXR plays a protective role in AA-induced AKI. First, PXR expression was dramatically decreased in mice and Boston University mouse proximal tubular (BUMPT) cells treated with AA. Overexpression of PXR in BUMPT cells alleviated apoptosis induced by AA. The specific agonist of PXR pregnenolone carbonitrile (PCN) relieved AA-induced AKI in mice, while the PXR inhibitor ketoconazole exacerbated the damage caused by AA in mice. Mechanistically, PXR bound to p53 in BUMPT cells and led to the ubiquitination and degradation of p53, thereby downregulating its expression. Taken as a whole, our data demonstrate that PXR may protect against AA-induced AKI by suppressing p53 expression.