Astragaloside IV Blunts Epithelial-Mesenchymal Transition and G2/M Arrest to Alleviate Renal Fibrosis via Regulating ALDH2-Mediated Autophagy

作者全名："Li, Dong; Liu, Yuzhe; Zhan, Quancao; Zeng, Yan; Peng, Ze; He, Qifeng; Tan, Qi; Cao, Wenfu; Wang, Shang; Wang, Jianwei"

作者地址："[Li, Dong; Liu, Yuzhe; Zhan, Quancao; Zeng, Yan; Peng, Ze; He, Qifeng; Tan, Qi; Cao, Wenfu; Wang, Shang; Wang, Jianwei] Chongqing Med Univ, Coll Tradit Chinese Med, Chongqing Key Lab Tradit Chinese Med Prevent & Cur, Chongqing 400016, Peoples R China; [Liu, Yuzhe; Zeng, Yan; He, Qifeng] Chongqing Med Univ, Coll Basic Med Sci, Chongqing 400016, Peoples R China"

通信作者："Wang, S; Wang, JW (通讯作者)，Chongqing Med Univ, Coll Tradit Chinese Med, Chongqing Key Lab Tradit Chinese Med Prevent & Cur, Chongqing 400016, Peoples R China."

来源：CELLS

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001030113100001

JCR分区：Q2

影响因子：5.1

年份：2023

卷号：12

期号：13

开始页：　

结束页：　

文献类型：Article

关键词：renal fibrosis; astragaloside IV; ALDH2; autophagy; AKT; mTOR

摘要："Previous studies show that astragaloside IV (ASIV) has anti-renal fibrosis effects. However, its mechanism remains elusive. In this study, we investigated the anti-fibrosis mechanisms of ASIV on chronic kidney disease (CKD) in vivo and in vitro. A CKD model was induced in rats with adenine (200 mg/kg/d, i.g.), and an in vitro renal fibrosis model was induced in human kidney-2 (HK-2) cells treated with TGF-& beta;1. We revealed that ASIV significantly alleviated renal fibrosis by suppressing the expressions of epithelial-mesenchymal transition (EMT)-related proteins, including fibronectin, vimentin, and alpha-smooth muscle actin (& alpha;-SMA), and G2/M arrest-related proteins, including phosphorylated p53 (p-p53), p21, phosphorylated histone H3 (p-H3), and Ki67 in both of the in vivo and in vitro models. Transcriptomic analysis and subsequent validation showed that ASIV rescued ALDH2 expression and inhibited AKT/mTOR-mediated autophagy. Furthermore, in ALDH2-knockdown HK-2 cells, ASIV failed to inhibit AKT/mTOR-mediated autophagy and could not blunt EMT and G2/M arrest. In addition, we further demonstrated that rapamycin, an autophagy inducer, reversed the treatment of ASIV by promoting autophagy in TGF-& beta;1-treated HK-2 cells. A dual-luciferase report assay indicated that ASIV enhanced the transcriptional activity of the ALDH2 promoter. In addition, a further molecular docking analysis showed the potential interaction of ALDH2 and ASIV. Collectively, our data indicate that ALDH2-mediated autophagy may be a novel target in treating renal fibrosis in CKD models, and ASIV may be an effective targeted drug for ALDH2, which illuminate a new insight into the treatment of renal fibrosis and provide new evidence of pharmacology to elucidate the anti-fibrosis mechanism of ASIV in treating renal fibrosis."

基金机构：Innovation Team Program of Chongqing Traditional Chinese Medicine [11500000MB1670604W/2022-00432]; Xinglin Program of Chongqing TCM/TCM-integrated Key discipline [2021-ZDXK-D03]

基金资助正文：This work was supported by Innovation Team Program of Chongqing Traditional Chinese Medicine (11500000MB1670604W/2022-00432) and Xinglin Program of Chongqing TCM/TCM-integrated Key discipline (2021-ZDXK-D03).