Novel poricoic acids attenuate renal fibrosis through regulating redox signalling and aryl hydrocarbon receptor activation
Novel poricoic acids attenuate renal fibrosis through regulating redox signalling and aryl hydrocarbon receptor activation
复制标题
新型硼酸通过调节氧化还原信号和芳烃受体激活来减轻肾纤维化
DOI：
10.1016/j.phymed.2020.153323
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发表时间：
2020-12-01
期刊：
影响因子：
7.9
通讯作者：
Zhao Ying-Yong
中科院分区：
文献类型：
--
作者：
Wang Ming;Hu He-He;Zhao Ying-Yong
背景：肾纤维化是慢性肾脏病（CKD）的最终表现。肾纤维化主要是由氧化应激和炎症驱动的。目的：本研究的目的是从茯苓中鉴定新的多孔酸，并研究其抗纤维化作用及其机制。方法：在本研究中，我们从茯苓中鉴定了六种新的多孔酸，并使用转化生长因子β 1-结果：6种尿酸均能显著抑制TGF-β 1诱导的HK-2细胞α-平滑肌肌动蛋白（α-smooth muscle actin，α-smooth muscle actin）的表达。3个C-3位羧基完整的化合物的抑菌效果比3个C-3位羧基酯化的化合物强。机械地说，多孔酸ZM（PZM）和多孔酸ZP（PZP）通过调节氧化还原信号传导（包括抑制促炎性核因子κ B）来减轻肾纤维化NF-κ B（NF-kappa B）信号转导及其靶基因以及抗氧化核因子-红细胞2相关因子2（Nrf 2）信号转导及其下游靶基因的激活在TGF-β 1诱导的HK-2和HK-2细胞中的表达。2细胞和UUO小鼠。PZM处理和PZP处理抑制上调的芳基烃受体，并且它们靶向UUO小鼠中的基因表达。有趣的是，PZM处理表现出比PZP处理更强的抑制作用。结构-功能关系分析表明，开环甾烷四环三萜类化合物中C-3位羧基是其抗肾纤维化的主要活性基团。结论：PZM和PZP通过调节氧化还原信号通路和芳香烃受体信号通路减轻肾纤维化。我们的研究结果将提供几个有前途的领导化合物对肾纤维化。
Background: Renal fibrosis is the final manifestation of chronic kidney disease (CKD). Renal fibrosis is largely driven by oxidative stress and inflammation.Purpose: The aim of the current study was to identify novel poricoic acids from Poria cocos and investigated their antifibrotic effects and the underlying mechanism.Methods: In this study, we identified six novel poricoic acids from Poria cocos and examined their antifibrotic effect using transforming growth factor-beta 1- (TGF-beta 1-) induced cultured human kidney proximal tubular epithelial cells (HK-2) and mice with unilateral ureteral obstruction (UUO).Results: Treatment with six poricoic acids significantly inhibited TGF-beta 1-induced a-smooth muscle actin expression at both mRNA and protein levels in HK-2 cells. Three compounds with an intact carboxyl group at C-3 position showed a stronger inhibitory effect than that of other three compounds with esterified carboxyl group at the C-3 position. Mechanistically, poricoic acid ZM (PZM) and poricoic acid ZP (PZP) attenuate renal fibrosis through the modulation of redox signalling including the inhibition of proinflammatory nuclear factor kappa B (NF-kappa B) signalling and its target genes as well as the activation of antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) signalling and its downstream target gene in both TGF-beta 1-induced HK-2 cells and UUO mice. PZM treatment and PZP treatment inhibit the upregulated aryl hydrocarbon receptor and they target the gene expression in UUO mice. Intriguingly, PZM treatment exhibits a stronger inhibitory effect than that of the PZP treatment. Structure-function relationship reveals that the carboxyl group at C-3 position is the most important bioactive function group in secolanostane tetracyclic triterpenoids against renal fibrosis.Conclusions: PZM and PZP attenuated renal fibrosis through the modulation of redox signalling and the aryl hydrocarbon receptor signalling pathway. Our findings will provide several promising leading compounds against renal fibrosis.