PXR/Akr1b7通路在急性肾小管损伤中的作用及机制研究

Acute kidney injury (AKI) is a series of clinical syndrome featured with high incidence, high morbidity, and high mortality. However，the pathogenic mechanism of AKI is still elusive. We also lack the effective therapeutic strategies for AKI. Thus, investigating the molecular mechanisms of AKI is of vital importance for the development of novel therapies. Nuclear receptor pregnane X receptor (PXR) regulates the expression of detoxifying enzymes and transporters, however, its role in AKI is unknown. By analyzing Nephroseq database, PXR showed reduced expression in the transplanted kidneys with rejection-induced injury. Meanwhile, we also found a significant reduction of PXR in kidneys of AKI patients, and AKI mice model and cells model. Importantly, pharmacological activation of PXR improved the renal function and pathological changes in AKI mice model and blocked apoptosis of renal tubular cells induced by cisplatin. These data suggested a protective role of PXR in AKI. Recently, it was reported that Akr1b7, an isotope of aldo-keto reductase regulating oxidative stress, was a target gene of PXR. Here we also found that Akr1b7 was downregulated in AKI models both in vivo and in vitro. Overexpression of Akr1b7 blocked cisplatin-induced apoptosis of renal tubular cells. Furthermore, modulation of PXR also altered the mRNA expression of Akr1b7 and autophagic protein LC3B. Above-mentioned data indicated that PXR could have a protective role in AKI by targeting Akr1b7-mediated autophagy. In the present proposal, employing the genetic and pharmacological approaches, we will fully investigate the role of PXR/ AKR1B7 pathway in the pathogenesis of AKI.

急性肾损伤（AKI）具有临床高发且致死率高等特点，但机制尚不十分清楚，也缺乏满意的干预手段。核受体PXR在多种脏器中发挥重要的生理及病理作用，但在AKI中尚无报道。PXR在有排斥损伤的移植肾表达降低，在AKI患者和动物肾脏及细胞模型也显著下调；PXR激动剂可改善AKI小鼠的肾功能及肾小管细胞凋亡，提示PXR在AKI中具有保护作用。新近发现，醛酮还原酶Akr1b7作为PXR靶基因，具有肝脏保护作用，但在肾脏中的作用尚不清楚。与PXR相一致，Akr1b7在AKI体内、外模型均显著下调，过表达Akr1b7减轻了顺铂诱导的细胞凋亡，过表达或敲低PXR也相应改变了Akr1b7以及自噬相关蛋白LC3B的表达，提示Akr1b7作为PXR的下游靶基因通过调控自噬介导了PXR在AKI的保护作用。本课题将在动物、细胞和分子水平深入研究PXR/Akr1b7通路在AKI中的作用，为临床防治AKI提供新视点。

急性肾损伤（AKI）具有临床高发且致死率高等特点，但机制尚不十分清楚，也缺乏满意的干预手段。核受体PXR在多种脏器中发挥重要的生理及病理作用，但在AKI中尚无报道。我们的前期研究结果提示PXR通过Akr1b7，调控自噬介导了PXR在AKI的保护作用。在本项目中，我们首先在AKI病人样本中证明了PXR蛋白水平与AKI病人肾功能负相关，在AKI动物模型中也显著下降。在顺铂诱导的AKI模型中，PXR基因敲除大鼠出现了更严重的急性肾小管损伤，并伴有严重的线粒体损伤；PXR激动剂PCN则可缓解顺铂诱导的急性肾损伤。这些结果证明PXR对AKI有重要作用，激活PXR可改善AKI。通过荧光素酶报告基因试验、基因干预和蛋白质组学研究，我们证明了PXR通过AKR1B7来调节线粒体，从而改善急性肾小管损伤。进一步，我们研究了Akr1b7在顺铂诱导肾小管上皮细胞损伤模型中的作用，并探索了其对线粒体的调节作用。同时，我们也研究了PXR对缺血/再灌注模型（I/R）诱导的AKI的作用。