Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis
Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis
复制标题
用白术内酯 I 抑制增殖相关信号级联反应可减少肌成纤维细胞表型和肾纤维化
DOI：
10.1016/j.bcp.2020.114344
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发表时间：
2021-01-01
影响因子：
5.8
通讯作者：
Bai, Yongheng
中科院分区：
文献类型：
--
作者：
Guo, Yangyang;Xiao, Yanyi;Bai, Yongheng
肾纤维化是导致终末期肾病发生的一个常见因素。苍术内酯I （ATL-1）是一种从苍术中提取的天然化合物，具有抗癌和抗氧化作用。然而，其抗肾纤维化作用尚不清楚。本研究通过体外tgf - β 1触发的成纤维细胞、小管上皮细胞（TECs）以及单侧输尿管梗阻（UUO）小鼠模型检测了ATL-1的抗纤维化作用。我们发现ATL-1通过靶向成纤维细胞-肌成纤维细胞分化（FMD）以及上皮-间质转化（EMT），抑制UUO肾脏的肌成纤维细胞表型和纤维化发展。ATL-1的抗纤维化作用与间质和小管细胞生长减少有关，导致由JAK2/STAT3、PI3K/Akt、p38 MAPK和Wnt/ β -catenin通路组成的增殖相关级联活性受到抑制。此外，ATL-1治疗通过拮抗增殖相关级联反应的激活，抑制了tgf - β 1触发的FMD和成纤维细胞中的肌成纤维细胞表型。同样，tgf - β 1引发tec中增殖相关信号的过度激活，引发EMT。肌成纤维细胞表型被ATL-1抑制。ATL-1的抗纤维化和抗增殖作用与Smad2/3信号失活有关，部分逆转FMD，以及EMT和肌成纤维细胞表型的抑制。因此，通过ATL-1的增殖相关级联反应，在体内和体外抑制肌成纤维细胞表型和纤维化的发展，使其成为预防肾纤维化的前瞻性治疗生物制剂。
Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide I (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anticancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-beta 1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/beta-catenin pathways. Besides, ATL-1 treatment repressed TGF-beta 1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-beta 1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.