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  3. New mechanism of nephrotoxicity of triptolide: Oxidative stress promotes cGAS-STING signaling pathway

New mechanism of nephrotoxicity of triptolide: Oxidative stress promotes cGAS-STING signaling pathway

  • Free Radic Biol Med. 2022 Aug 1;188:26-34. doi: 10.1016/j.freeradbiomed.2022.06.009.
Jun Lu 1,  Yi Zhang 2,  Huiyue Dong 3,  Jingjing Sun 4,  Ling Zhu 3,  Pengyang Liu 3,  Fuli Wen 3,  Rong Lin 3
Affiliations

Affiliations

  • 1 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. Electronic address: junlu.heather@xmu.edu.cn.
  • 2 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.
  • 3 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.
  • 4 Laboratory of Basic Medicine, Dongfang Hospital (900th Hospital of the Joint Logistics Team), Xiamen University, Fuzhou, 350025, China.
PMID: 35697291 DOI: 10.1016/j.freeradbiomed.2022.06.009
Abstract

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.

Keywords

BACH1; Oxidative stress; Renal injury; STING; Triptolide.

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