Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, People's Republic of China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, People's Republic of China.
Am J Physiol Renal Physiol. 2021 Nov 1;321(5):F617-F628. doi: 10.1152/ajprenal.00193.2021. Epub 2021 Sep 27.
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 () 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 , 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 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. 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 , 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.
配体激活的核受体法尼醇 X 受体（FXR）在调节肾功能方面发挥着关键作用。其特异性激动剂激活 FXR 可在急性肾损伤（AKI）动物中发挥肾保护作用。本研究旨在鉴定具有治疗肾缺血再灌注损伤潜力的天然 FXR 激动剂。通过双荧光素酶报告基因分析、对接分析、定点突变和全肾转录组分析来确定 FXR 的体外和体内激活情况。使用野生型（WT）和 FXR 敲除（）小鼠来确定潜在 FXR 激动剂对肾缺血再灌注损伤（IRI）的影响。我们发现，从一种著名的中药中提取的主要活性三萜类化合物泽泻醇 B-23-醋酸酯（ABA）可以激活肾脏 FXR，并诱导小鼠肾脏中 FXR 下游基因的表达。ABA 处理显著减轻了 WT 小鼠但不能减轻 小鼠的肾缺血再灌注引起的 AKI。我们的结果表明，ABA 可以激活肾脏 FXR 发挥对缺血再灌注损伤引起的 AKI 的肾保护作用。因此，ABA 可能代表治疗缺血性 AKI 的潜在治疗剂。在本研究中，我们发现从泽泻中鉴定出的天然法尼醇 X 受体（FXR）激动剂泽泻醇 B-23-醋酸酯（ABA）通过改善肾功能、减少肾小管细胞凋亡、改善氧化应激和抑制炎症因子表达，以 FXR 依赖性方式保护缺血性急性肾损伤（AKI）。因此，ABA 将来可能具有作为 AKI 治疗的新型治疗剂的巨大潜力。
