Farnesoid X receptor promotes renal ischaemia-reperfusion injury by inducing tubular epithelial cell apoptosis.
Farnesoid X receptor promotes renal ischaemia-reperfusion injury by inducing tubular epithelial cell apoptosis.
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法尼醇X受体通过诱导肾小管上皮细胞凋亡促进肾缺血再灌注损伤
DOI：
10.1111/cpr.13005
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发表时间：
2021-04
影响因子：
8.5
通讯作者：
Mou S
中科院分区：
文献类型：
--
作者：
Xu Y;Li D;Wu J;Zhang M;Shao X;Xu L;Tang L;Zhu M;Ni Z;Zhang M;Mou S
我们研究了法尼醇X受体（FXR），一种配体依赖性转录因子，在肾缺血再灌注（I/R）损伤中的作用。我们在体内在FXR敲除（Fxr−/−）和野生型（WT）小鼠中进行了单侧肾I/R模型，并在体外进行了缺氧-复氧（H/R）模型。使用蛋白质组分析仪阵列检测FXR诱导细胞凋亡的途径。采用免疫印迹法、TUNEL法和流式细胞术评价FXR对细胞凋亡的影响。与WT小鼠相比，Fxr−/−小鼠表现出肾功能改善，肾小管损伤评分和细胞凋亡减少。与体内结果一致，FXR的沉默减少了H/R后HK-2细胞凋亡的数量，而FXR过表达加重了凋亡。值得注意的是，骨髓移植（BMT）和免疫组化实验揭示了FXR参与肾小管上皮细胞，而不是炎症细胞。此外，体内和体外研究表明，FXR缺乏增加了肾脏中磷酸化Bcl-2细胞死亡激动剂（p-Bad）表达水平和Bcl-2/Bcl-xL与Bax表达的比率。wortmannin治疗，减少了p-Bad表达，抑制了FXR缺乏的影响，消除了Fxr−/−小鼠肾脏对I/R损伤的耐受性。这些结果确立了I/R损伤后肾小管上皮细胞中FXR失活的关键重要性。FXR可能通过抑制PI 3 k/Akt-介导的Bad磷酸化，促进肾小管上皮细胞凋亡，从而引起肾I/R损伤。我们发现FXR在肾小管上皮细胞的生存信号和死亡调节中的重要作用，为FXR作为肾脏生物学的重要调节因子提供了支持。提示FXR参与了肾I/R损伤，可能成为阿基的治疗靶点。
We investigated the role of farnesoid X receptor (FXR), a ligand‐dependent transcription factor, in renal ischaemia‐reperfusion (I/R) injury. We performed unilateral renal I/R model in FXR knockout (Fxr−/−) and wild‐type (WT) mice in vivo and a hypoxia‐reoxygenation (H/R) model in vitro. The pathways by which FXR induces apoptosis were detected using a proteome profiler array. The effects of FXR on apoptosis were evaluated using immunoblotting, TUNEL assays and flow cytometry. Compared with WT mice, Fxr−/− mice showed improved renal function and reduced tubular injury scores and apoptosis. Consistent with the in vivo results, the silencing of FXR decreased the number of apoptotic HK‐2 cells after H/R, while FXR overexpression aggravated apoptosis. Notably, bone marrow transplantation (BMT) and immunohistochemistry experiments revealed the involvement of FXR in the tubular epithelium rather than in inflammatory cells. Furthermore, in vivo and in vitro studies demonstrated that FXR deficiency increased phosphorylated Bcl‐2 agonist of cell death (p‐Bad) expression levels and the ratio of Bcl‐2/Bcl‐xL to Bax expression in the kidney. Treatment with wortmannin, which reduced p‐Bad expression, inhibited the effects of FXR deficiency and eliminated the tolerance of Fxr−/− mouse kidneys to I/R injury. These results established the pivotal importance of FXR inactivation in tubular epithelial cells after I/R injury. FXR may promote the apoptosis of renal tubular epithelial cells by inhibiting PI3k/Akt‐mediated Bad phosphorylation to cause renal I/R damage. We found the important role of FXR in survival signalling and death regulation in renal tubular epithelium, providing support for FXR as a vital regulator of renal biology. It suggested that FXR participated in renal I/R injury and could be a therapeutic target for AKI.
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