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丹酚酸 A 通过激活 Akt/mTOR/4EBP1 信号通路改善肾缺血再灌注损伤。

Salvianolic acid A ameliorates renal ischemia/reperfusion injury by activating Akt/mTOR/4EBP1 signaling pathway.

机构信息

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.

Department of Pharmacy, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.

出版信息

Am J Physiol Renal Physiol. 2018 Aug 1;315(2):F254-F262. doi: 10.1152/ajprenal.00508.2017. Epub 2018 Jan 31.

Abstract

Salvianolic acid A (Sal A) has been shown to prevent and treat ischemic cardiovascular, as well as cerebral vascular diseases. However, little is known about Sal A in renal ischemia/reperfusion (I/R) injury. In this study, a renal I/R injury model in rats and a hypoxia/reoxygenation (H/R) model to damage proximal renal tubular cells (HK-2) were used to assess whether Sal A halts the development and progression of renal I/R injury. As compared with vehicle treatment, Sal A significantly attenuated kidney injury after renal I/R injury, accompanied by decreases in plasma creatinine, blood urea nitrogen levels, the number of apoptosis-positive tubular cells, and kidney oxidative stress. Sal A also activated phosphorylated protein kinase B (p-Akt) and phosphorylated-mammalian target of rapamycin (p-mTOR) compared with vehicle-treated I/R injury rats. In H/R-injured HK-2 cells, Sal A can reduce the levels of reactive oxygen species in a dose-related manner. Similar to the results from in vivo experiments, in vitro Sal A also increased the protein expression of phosphorylated-eukaryotic initiation factor 4E binding protein 1 (p-4EBP1) compared with vehicle. Furthermore, the cytoprotective activity of Sal A was inhibited by LY294002 and rapamycin. These findings indicate that Sal A can ameliorate renal I/R injury and promote tubular cell survival partly via the Akt/mTOR/4EBP1pathway. Sal A could be a candidate compound to prevent ischemic tissue damage.

摘要

丹酚酸 A(Sal A)已被证明可预防和治疗缺血性心血管病和脑血管病。然而,Sal A 对肾缺血/再灌注(I/R)损伤的作用知之甚少。本研究采用大鼠肾 I/R 损伤模型和缺氧/复氧(H/R)损伤近端肾小管细胞(HK-2)模型,评估 Sal A 是否能阻止肾 I/R 损伤的发生和进展。与载体处理相比,Sal A 可显著减轻肾 I/R 损伤后的肾损伤,同时降低血浆肌酐、血尿素氮水平、凋亡阳性肾小管细胞数量和肾氧化应激。Sal A 还可激活磷酸化蛋白激酶 B(p-Akt)和磷酸化哺乳动物雷帕霉素靶蛋白(p-mTOR),与载体处理的 I/R 损伤大鼠相比。在 H/R 损伤的 HK-2 细胞中,Sal A 可呈剂量依赖性降低活性氧水平。与体内实验结果相似,体外 Sal A 也可增加磷酸化真核起始因子 4E 结合蛋白 1(p-4EBP1)的蛋白表达,与载体相比。此外,Sal A 的细胞保护活性被 LY294002 和雷帕霉素抑制。这些发现表明,Sal A 可通过 Akt/mTOR/4EBP1 通路改善肾 I/R 损伤和促进肾小管细胞存活,Sal A 可能是预防缺血性组织损伤的候选化合物。

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