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.

中文翻译：

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天然存在的 FXR 激动剂 Alisol B 23-acetate 可防止肾缺血再灌注损伤。


配体激活的核受体法尼醇 X 受体 (FXR) 在调节肾功能中发挥着关键作用。 FXR 的特异性激动剂激活可对患有急性肾损伤 (AKI) 的动物发挥肾脏保护作用。在本研究中，我们的目的是鉴定天然存在的 FXR 激动剂，其具有作为肾缺血再灌注损伤治疗剂的潜力。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来确定体外和体内 FXR 激活。使用野生型 (WT) 和 FXR 敲除 (FXR-/-) 小鼠来确定潜在 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（ABA）是从著名中药泽泻中提取的一种主要活性三萜类化合物，可以激活肾FXR并诱导小鼠肾脏中FXR下游基因的表达。 ABA 治疗显着减轻了 WT 小鼠肾缺血再灌注引起的 AKI，但对 FXR-/- 小鼠没有影响。我们的结果表明，ABA 可以激活肾脏 FXR，对缺血再灌注损伤诱导的 AKI 发挥肾脏保护作用。因此，ABA 可能是治疗缺血性 AKI 的潜在治疗剂。 新颖和值得注意的是 在本研究中，我们发现泽泻醇 B 23-乙酸酯 (ABA) 是一种已鉴定的天然法尼醇 X 受体 (FXR) 激动剂，来自于已知的中药泽泻以 FXR 依赖性方式预防缺血性急性肾损伤 (AKI)，表现为改善肾功能、减少肾小管凋亡、改善氧化应激和抑制炎症因子表达。 因此，ABA作为未来治疗AKI的新型治疗剂可能具有巨大的潜力。