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-乙酸酯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) 在调节肾功能中起着关键作用。FXR 通过其特定激动剂的激活对患有急性肾损伤 (AKI) 的动物具有肾脏保护作用。在本研究中，我们的目的是确定天然存在的 FXR 激动剂，其具有作为肾缺血再灌注损伤治疗剂的潜力。体外和体内 FXR 激活由双荧光素酶测定、对接分析、定点诱变和全肾转录组分析确定。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) 的影响。我们发现 alisol B 23-acetate (ABA) 是一种从著名中药泽泻中提取的主要活性三萜，可以激活肾脏 FXR 并诱导小鼠肾脏中 FXR 下游基因的表达。ABA 治疗显着减弱了 WT 小鼠中肾缺血再灌注诱导的 AKI，但在 FXR-/- 小鼠中没有。我们的结果表明，ABA 可以激活肾脏 FXR 以对缺血再灌注损伤诱导的 AKI 发挥肾脏保护作用。因此，ABA 可能代表了治疗缺血性 AKI 的潜在治疗剂。新的和值得注意的在本研究中，我们发现 alisol B 23-乙酸 (ABA)，一种已鉴定的天然法尼醇 X 受体 (FXR) 激动剂来自已知中药泽泻以 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。