Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice

Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many other...

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Published inBiochimica et biophysica acta. Molecular basis of disease Vol. 1867; no. 3; p. 165996
Main Authors Luan, Zhilin, Wei, Yuanyi, Huo, Xiaoxiao, Sun, Xiaowan, Zhang, Cong, Ming, Wenhua, Luo, Zhaokang, Du, Chunxiu, Li, Yaqing, Xu, Hu, Lu, Heyuan, Zheng, Feng, Guan, Youfei, Zhang, Xiaoyan
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.03.2021
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Summary:Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many other functions including the regulation of cell proliferation, inflammatory response, and glucose and lipid metabolism. In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity in mice. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α‑carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory gene expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways, especially the PI3K/AKT pathway. In vitro study further revealed that PXR protected against cisplatin-induced apoptosis of cultured proximal tubule cells in a PI3K-dependent manner. Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel protective target for cisplatin-induced nephrotoxicity. •Renal toxicity is a severe complication of cisplatin treatment.•Accumulating evidence indicates that PXR may act as a critical regulatory factor in renal physiology and pathophysiology.•The nuclear receptor PXR protects against cisplatin-induced acute kidney injury (AKI) through the PI3K/AKT pathway.•Our findings suggest the potential of PXR as a novel therapeutic target for drug-induced nephrotoxicity.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2020.165996