Effects and molecular mechanism of pachymic acid on ferroptosis in renal ischemia reperfusion injury
Effects and molecular mechanism of pachymic acid on ferroptosis in renal ischemia reperfusion injury
复制标题
茯苓酸对肾缺血再灌注损伤铁死亡的影响及分子机制
DOI：
10.3892/mmr.2020.11704
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发表时间：
2021-01-01
影响因子：
3.4
通讯作者：
Liao, Xiao-Hui
中科院分区：
文献类型：
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作者：
Jiang, Gui-Ping;Liao, Yue-Juan;Liao, Xiao-Hui
急性肾损伤(AKI)是临床常见病。铁缺乏症是一种新型的调节性细胞死亡，在AKI中起着重要的调节作用。孔雀酸(PA)是茯苓中的一种羊毛甾烷型三萜类化合物，已被报道对AKI具有保护作用。然而，PA在AKI中的保护机制尚不完全清楚。本研究旨在探讨PA对在体肾缺血再灌注损伤中铁下垂的影响及其分子机制。30只小鼠分别腹腔注射PA 5、10、20 mg/kg，连续3d。采用双侧肾蒂夹夹40min复制大鼠肾缺血再灌注损伤模型。结果表明，PA治疗可降低血肌酐和尿素氮，减轻肾脏病理损害。透射电子显微镜显示，高剂量PA组大鼠肾组织线粒体铁性下垂无特征性改变，仅有轻度水肿。此外，PA还能增加肾脏谷胱甘肽的表达，降低丙二醛和环氧合酶2的表达水平。PA还能增强肾脏中铁下垂相关蛋白谷胱甘肽过氧化物酶4(Gpx4)、溶质载体家族7(阳离子氨基酸转运体，y+系统)成员11(SLC7A11)和血红素加氧酶1(HO-1)的蛋白和mRNA表达水平，并增加核因子红系衍生2(NRF2)信号通路成员的表达水平。综上所述，本研究结果提示PA对小鼠缺血再灌注性急性肾损伤具有保护作用，其机制可能与直接或间接激活NRF2抑制肾脏铁下垂，上调下游铁下垂相关蛋白Gpx4、SLC7A11和HO-1的表达有关。
Acute kidney injury (AKI) is a common clinical disease. Ferropotosis, a new type of regulatory cell death, serves an important regulatory role in AKI. Pachymic acid (PA), a lanostane-type triterpenoid from Poria cocos, has been reported to be protective against AKI. However, the protective mechanism of PA in AKI is not yet fully understood. The present study aimed to investigate the effect and molecular mechanism of PA on ferroptosis in renal ischemia reperfusion injury in vivo. A total of 30 mice were intraperitoneally injected with 5, 10 and 20 mg/kg PA for 3 days. A bilateral renal pedicle clip was used for 40 min to induce renal ischemia-reperfusion injury and establish the model. The results demonstrated that treatment with PA decreased serum creatinine and blood urea nitrogen, and ameliorated renal pathological damage. Transmission electron microscopy revealed no characteristic changes in ferroptosis in the mitochondria of the renal tissue in the high-dose PA group, and only mild edema. Furthermore, treatment with PA increased glutathione expression, and decreased the expression levels of malondialdehyde and cyclooxygenase 2. Treatment with PA enhanced the protein and mRNA expression levels of the ferroptosis related proteins, glutathione peroxidase 4 (GPX4), solute carrier family 7 (cationic amino acid transporter, y+ system) member 11 (SLC7A11) and heme oxygenase 1 (HO-1) in the kidney, and increased the expression levels of nuclear factor erythroid derived 2 like 2 (NRF2) signaling pathway members. Taken together, the results of the present study suggest that PA has a protective effect on ischemia-reperfusion induced acute kidney injury in mice, which may be associated with the inhibition of ferroptosis in the kidneys through direct or indirect activation of NRF2, and upregulation of the expression of the downstream ferroptosis related proteins, GPX4, SLC7A11 and HO-1.