Alisol A 24-Acetate and Alisol B 23-Acetate Induced Autophagy Mediates Apoptosis and Nephrotoxicity in Human Renal Proximal Tubular Cells.
Alisol A 24-Acetate and Alisol B 23-Acetate Induced Autophagy Mediates Apoptosis and Nephrotoxicity in Human Renal Proximal Tubular Cells.
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Alisol A 24-Acetate 和 Alisol B 23-Acetate 诱导的自噬介导人肾近端管状细胞的凋亡和肾毒性
DOI：
10.3389/fphar.2017.00172
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发表时间：
2017
影响因子：
5.6
通讯作者：
Jia X
中科院分区：
文献类型：
--
作者：
Wang C;Feng L;Ma L;Chen H;Tan X;Hou X;Song J;Cui L;Liu D;Chen J;Yang N;Wang J;Liu Y;Zhao B;Wang G;Zhou Y;Jia X
泽泻中含有丰富的泽泻醇A 24-乙酸酯（24 A）和泽泻醇B 23-乙酸酯（23 B）。本研究旨在探讨24 A和23 B对人肾小管上皮细胞（HK-2）自噬的诱导作用及其对PI 3 K/Akt/mTOR信号通路的调节作用。目前，三萜素、Kim-1和TFF-3被认为是新的肾毒性生物指示剂。有趣的是，在体内和体外，23 B和24 A可以显著增加Escherin、Kim-1和TFF-3的蛋白表达和mRNA水平。23 B和24 A可通过显著降低Bcl-2和Bcl-xl的蛋白表达和mRNA水平来诱导细胞凋亡。23 B和24 A均能诱导HK-2细胞自噬，其机制可能与增加LC 3 II/LC 3 I比值、Beclin-1蛋白表达以及LC 3和Beclin-1 mRNA水平有关。同时，这两种化合物对PI 3 K/Akt/mTOR信号通路均有抑制作用。自噬抑制剂3-甲基腺嘌呤可以部分逆转细胞活力，并相反地改变LC 3 II/LC 3 I的比例以及Bcl-2和Kim-1的蛋白表达。因此，本研究有助于了解23 B和24 A通过抑制PI 3 K/Akt/mTOR信号通路诱导自噬导致细胞凋亡和肾毒性，为进一步研究这两种化合物的肾毒性提供了理论依据，也为泽泻的临床安全使用提供了参考。
Two natural compounds alisol A 24-acetate (24A) and alisol B 23-acetate (23B) are abundant in Rhizoma alismatis. In the present study, we evaluated the induction of 24A and 23B on apoptosis and possible nephrotoxicity of human renal proximal tubular (HK-2) cells by activating autophagy and also explored its regulation on PI3K/Akt/mTOR signaling pathway. Presently, Clusterin, Kim-1, and TFF-3 were considered to be new bioindicators of nephrotoxicity. Interestingly, the protein expression and mRNA levels of Clusterin, Kim-1 and TFF-3 could be significantly increased by 23B and 24A in vivo and in vitro. Furthermore, cell apoptosis could be triggered by 23B and 24A via significantly decreasing the protein expression and mRNA levels of Bcl-2 and Bcl-xl. Autophagy of HK-2 cells could be induced by both 23B and 24A via significantly enhancing the ratio of LC3II/LC3I, the protein expression of Beclin-1 as well as the mRNA levels of LC3 and Beclin-1. Meanwhile, PI3K/Akt/mTOR signaling pathway could be inhibited by these two compounds. An autophagy inhibitor, 3-methyladenine, could partially reverse cell viability and conversely change the ratio of LC3II/LC3I and the protein expression of Bcl-2 and Kim-1. Thus this study helped to understand that 23B and 24A induced autophagy resulted in apoptosis and nephrotoxicity through inhibiting PI3K/Akt/mTOR signaling pathway, facilitating further studies for nephrotoxicity induced by these two compounds and could be beneficial for safe use of Rhizoma alismatis in clinic.