Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice
Pregnane X receptor (PXR) protects against cisplatin-induced acute kidney injury in mice
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DOI：
10.1016/j.bbadis.2020.165996
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发表时间：
2021-01-23
影响因子：
6.2
通讯作者：
Zhang, Xiaoyan
中科院分区：
文献类型：
--
作者：
Luan, Zhilin;Wei, Yuanyi;Zhang, Xiaoyan
顺铂引起的急性肾损伤（CAKI）是顺铂最严重的副作用之一。孕烷X受体（PXR）是一种配体依赖性核受体，是生物外源性物质解毒的主要调节因子。越来越多的证据表明PXR还具有许多其他功能，包括调节细胞增殖、炎症反应以及葡萄糖和脂质代谢。在这项研究中，我们的目的是研究PXR在顺铂诱导的小鼠肾毒性中的作用。在野生型或PXR敲除小鼠中进行CAKI模型。孕烯醇酮16 α-甲腈（PCN），一种小鼠PXR特异性激动剂，用于PXR活化。在小鼠血液、尿液或肾组织中检查肾功能、生化、组织病理学和分子改变。通过RNA测序进行了全转录组分析。我们发现，PXR激活显着衰减CAKI反映改善肾功能，减少肾小管凋亡，改善氧化和内质网应激，抑制炎症基因表达。RNA测序分析表明PXR的肾保护作用与多种关键信号通路有关，尤其是PI 3 K/AKT通路。体外研究进一步显示PXR以PI 3 K依赖的方式保护顺铂诱导的培养近曲小管细胞凋亡。我们的研究结果表明，PXR激活可以保护顺铂诱导的阿基中的肾功能，并表明PXR作为顺铂诱导的肾毒性的新保护靶点的可能性。
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.