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

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1867

Article

Luan, Zhilin^1,2  Wei, Yuanyi^1,2  Huo, Xiaoxiao¹  Sun, Xiaowan¹  Zhang, Cong¹  Ming, Wenhua¹  Luo, Zhaokang¹  Du, Chunxiu¹  Li, Yaqing¹  Xu, Hu^1,2  Lu, Heyuan^1,2  Zheng, Feng¹  Guan, Youfei^1,2  Zhang, Xiaoyan^1,2 

[1] Dalian Med Univ, Adv Inst Med Sci, 9 W,S Lvshun Blvd, Dalian 116044, Peoples R China

[2] Dalian Med Univ, Sch Basic Med Sci, Dept Physiol & Pathophysiol, Dalian 116044, Peoples R China

关键词: Pregnane X receptor;    Acute kidney injury;    Cisplatin;    Nephrotoxicity;    PI3K/AKT pathway;   

DOI  :  10.1016/j.bbadis.2020.165996

来源: Elsevier

【 摘 要 】

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 16a-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 renopmtective 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.

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