核受体PXR在肾脏生理调节及急性肾损伤中的作用

急性肾损伤(AKI)是各种原因所致的以肾功能急剧下降为特征的临床综合征，危害严重。孕烷X受体(PXR)是一种核受体转录因子，可被众多内源和外源化合物激活，但存在显著种属差异。PXR通过调控其靶基因表达，保护组织器官免受有害物质损伤并维持机体内环境稳态。申请人前期研究发现，小鼠PXR广泛表达于肾脏各小管节段和集合管；其基因敲除导致尿量显著的增加；其激活可显著缓解缺血-再灌注所致AKI，提示PXR在肾脏生理调节及疾病发生中有重要作用。本项目旨在明确PXR的肾脏生理功能及在急性肾损伤中的作用。主要研究内容包括：1)明确人和小鼠PXR在肾脏的精确定位；2)使用PXR敲除和人源化小鼠探讨其在肾脏水盐转运调节中的作用和机制；3)使用PXR基因敲除和人源化小鼠确定其缓解AKI的作用及机理。本项目的完成将为阐明PXR的肾脏生理功能和对AKI的保护作用提供重要依据，也将为人类AKI的治疗提供新靶点。

Acute kidney injury (AKI) represents a clinical syndrome with a sharp decline in renal function mainly due to renal ischemia-reperfusion injury and drug-related nephrotoxicity. Its morbidity and mortality are high with worldwide growing burden on both affected individuals and healthcare systems. Pregnane X receptor (PXR), as a member of the ligand-activated transcription factor nuclear receptor superfamily, can be activated by numerous clinical drugs, environmental pollutants and plant extracts. Once activated, PXR regulates the expression of its downstream target genes to protect organs and tissues from harmful substances. In our previous study, we found that PXR was widely expressed in most of renal tubular segments in mice. PXR gene deficiency resulted in a marked increase in urine output. Activation of PXR protected the mice from AKI following renal ischemia and reperfusion. The present project aims to further explore the physiological function of PXR in the kidney and its protective role in AKI in both human and mouse. Three specific aims were proposed to define: 1) intra-renal distribution and precise localization of PXR in human and mouse kidney; 2) the role of PXR in the regulation of renal water and sodium reabsorption by using the PXR knockout mice and humanized PXR mice; 3) the role of PXR in attenuating ischemia-reperfusion and cisplatin-induced AKI in wild-type, PXR knockout and humanized PXR mice. The completion of the proposed project will not only help uncover the physiological function of PXR in the kidney, but also provide an important experimental basis for elucidating the role of PXR in the pathogenesis of AKI both in rodents and men.