Fujian Provincial Key Laboratory of Transplant Biology, Fuzong Clinical College, Fujian Medical University, Fuzhou, 350025, China; Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, 350025, China.
Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, 350025, China; Clinical Laboratory, Zhongshan Hospital, Xiamen University, Xiamen, 361004, China.
Free Radic Biol Med. 2022 Aug 1;188:26-34. doi: 10.1016/j.freeradbiomed.2022.06.009. Epub 2022 Jun 10.
Triptolide (TPL) is a bioactive component extracted from the traditional Chinese herb Tripterygium wilfordii Hook F., and has multiple pharmacological activities, such as anti-tumor activity. However, severe adverse effects and toxicity, especially nephrotoxicity, limit its clinical application. It has been demonstrated that mitochondrial defect is a major toxic effects of TPL. In this study, we show that triptolide activated the cGAS-STING signaling pathway in kidney tubular cells in vivo and in vitro. Renal injury models were established in BALB/c mice and human tubular epithelial cells using TPL. We found that TPL enhanced the phosphorylation levels of STING, TBK1 and IRF3, and upregulated the expression of IFNβ, which is the production of cGAS-STING signaling pathway. STING inhibitor C176 had protective effects in TPL-induced nephrocyte damage. STING siRNA down regulated the expression level of IFNβ. In addition, triptolide induced an increase in protein levels of the transcription factor BACH1, while transcriptional expression of the antioxidant enzyme HMOX1 was reduced due to the increased expression of BACH1. Furthermore, oxidative stress-induced mtDNA damage and DNA leakage caused activation of the cGAS-STING signaling pathway. Altogether, cGAS-STING signaling pathway involved in TPL induced nephrotoxicity. Inhibiting cGAS-STING over-activation may be a new strategy for alleviating renal injury of triptolide.
雷公藤红素（TPL）是从传统中药雷公藤中提取的生物活性成分，具有多种药理活性，如抗肿瘤活性。然而，严重的不良反应和毒性，特别是肾毒性，限制了其临床应用。已经证明，线粒体缺陷是 TPL 的主要毒性作用之一。在这项研究中，我们表明三萜内酯在体内和体外激活了肾小管细胞中的 cGAS-STING 信号通路。在 BALB/c 小鼠和人肾小管上皮细胞中使用 TPL 建立了肾损伤模型。我们发现 TPL 增强了 STING、TBK1 和 IRF3 的磷酸化水平，并上调了 IFNβ的表达，这是 cGAS-STING 信号通路的产物。STING 抑制剂 C176 在 TPL 诱导的肾细胞损伤中具有保护作用。STING siRNA 下调了 IFNβ的表达水平。此外，三萜内酯诱导转录因子 BACH1 的蛋白水平增加，而由于 BACH1 的表达增加，抗氧化酶 HMOX1 的转录表达减少。此外，氧化应激诱导的 mtDNA 损伤和 DNA 泄漏导致 cGAS-STING 信号通路的激活。总之，cGAS-STING 信号通路参与了 TPL 诱导的肾毒性。抑制 cGAS-STING 的过度激活可能是缓解三萜内酯肾损伤的一种新策略。
