A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury
A naturally occurring FXR agonist, alisol B 23-acetate, protects against renal ischemia-reperfusion injury
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DOI：
10.1152/ajprenal.00193.2021
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发表时间：
2021-11-01
影响因子：
4.2
通讯作者：
Zhang, Xiao-Yan
中科院分区：
文献类型：
--
作者：
Luan, Zhi-Lin;Ming, Wen-Hua;Zhang, Xiao-Yan
配体激活的核受体法尼醇X受体（FXR）在调节肾功能中起着关键作用。FXR通过其特异性激动剂的激活在急性肾损伤（阿基）动物中发挥肾保护作用。在本研究中，我们的目的是确定天然存在的FXR激动剂与潜在的治疗药物在肾缺血再灌注损伤。通过双荧光素酶测定、对接分析、定点诱变和全肾转录组分析确定体外和体内FXR活化。使用野生型（WT）和FXR敲除（FXR-/-）小鼠来确定潜在的FXR激动剂对肾缺血-再灌注损伤（IRI）的作用。我们发现泽泻醇B 23-乙酸酯（alisol B 23-acetate，阿坝）是从中药泽泻中提取的一种主要活性三萜类化合物，它能激活小鼠肾脏FXR并诱导FXR下游基因的表达。阿坝处理显著减弱WT小鼠中肾缺血-再灌注诱导的阿基，但在FXR-/-小鼠中没有。我们的研究结果表明，阿坝可以激活肾脏FXR对缺血再灌注损伤诱导的阿基发挥肾脏保护作用。因此，阿坝可能代表治疗缺血性阿基的潜在治疗剂。新&值得注意的是在本研究中，我们发现泽泻醇B 23-乙酸酯（阿坝），一种从著名的传统中药泽泻中鉴定的天然法尼醇X受体（FXR）激动剂，以FXR依赖性方式保护缺血性急性肾损伤（阿基），如肾功能改善所反映的，减少肾小管细胞凋亡，改善氧化应激，抑制炎症因子表达。因此，阿坝可能是一个新的治疗药物在治疗阿基的未来有很大的潜力。
The ligand-activated nuclear receptor, farnesoid X receptor (FXR), plays a pivotal role in regulating renal function. Activation of FXR by its specific agonists exerts renoprotective action in animals with acute kidney injury (AKI). In the present study, we aimed to identify naturally occurring agonists of FXR with potential as therapeutic agents in renal ischemia-reperfusion injury. In vitro and in vivo FXR activation was determined by a dual-luciferase assay, docking analysis, site-directed mutagenesis, and whole kidney transcriptome analysis. Wild-type (WT) and FXR knockout (FXR-/-) mice were used to determine the effect of potential FXR agonist on renal ischemia-reperfusion injury (IRI). We found that alisol B 23-acetate (ABA), a major active triterpenoid extracted from Alismatis rhizoma, a well-known traditional Chinese medicine, can activate renal FXR and induce FXR downstream gene expression in mouse kidney. ABA treatment significantly attenuated renal ischemia-reperfusion-induced AKI in WT mice but not in FXR-/- mice. Our results demonstrate that ABA can activate renal FXR to exert renoprotection against ischemia-reperfusion injury-induced AKI. Therefore, ABA may represent a potential therapeutic agent in the treatment of ischemic AKI.NEW & NOTEWORTHY In the present study, we found that alisol B 23-acetate (ABA), an identified natural farnesoid X receptor (FXR) agonist from the well-known traditional Chinese medicine Alismatis rhizoma, protects against ischemic acute kidney injury (AKI) in an FXR-dependent manner, as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative stress, and suppressed inflammatory factor expression. Therefore, ABA may have great potential as a novel therapeutic agent in the treatment of AKI in the future.