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Inhibition of cGAS-STING signaling pathway alleviates high glucose-induced mesothelial-mesenchymal transition in
Fuxing Dong1, Luli Zheng2, Fuyuan Hong3
1Department of Nephrology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China. fuxingdong2025@163.com.
Abstract:
The mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells is a critical factor contributing to the progression of peritoneal fibrosis. This study aimed to explore the effect of cGAS-STING signaling pathway on the MMT process in peritoneal mesothelial cells. The expressions of cGAS, STING, α-SMA, and Vimentin in HMrSV5 cells treated with high glucose were analyzed using WB. Subsequently, si-cGAS and the cGAS inhibitor RU.521 were employed to intervene in HMrSV5 cells. qPCR was utilized to evaluate the expression levels of genes involved in the cGAS-STING signaling pathway (cGAS, STING, IRF3, TBK1) and MMT-related genes (E-cadherin, Vimentin, α-SMA, TGF-β1). The protein expressions of the cGAS-STING signaling pathway and MMT-related proteins were detected by WB. The invasive capacity of cells in each cell was assessed using a Transwell assay, and the levels of pro-inflammatory cytokines (IL-6, TNF-α) in the supernatants of each cell were measured by ELISA. In the present study, we found that the expressions of cGAS, p-STING/STING, p-IRF3/IRF3, and p-TBK1/TBK1 proteins were significantly upregulated in HG-treated HMrSV5 cells. Furthermore, the activation of the cGAS-STING signaling pathway could be effectively suppressed in HMrSV5 cells transfected with si-cGAS or treated with RU.521. Additionally, treatment with si-cGAS or RU.521 not only attenuated the invasive capacity of HMrSV5 cells but also decreased the levels of pro-inflammatory cytokines and inhibited the expression of MMT-related markers. Suppression of the cGAS-STING signaling pathway mitigates HG-induced MMT in the human peritoneal mesothelial cell line HMrSV5.
Insights
High glucose induces peritoneal fibrosis by activating the cGAS-STING pathway in mesothelial cells. Inhibiting this pathway reduces fibrosis markers and inflammation, offering a potential therapeutic target for peritoneal fibrosis.
Area of Science:
- Cell Biology
- Immunology
- Renal Physiology
Background:
- Mesothelial-mesenchymal transition (MMT) drives peritoneal fibrosis.
- The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is implicated in inflammatory responses.
Purpose of the Study:
- To investigate the role of the cGAS-STING signaling pathway in high glucose-induced MMT in human peritoneal mesothelial cells (HMrSV5).
Main Methods:
- Western blotting (WB) to assess protein expression.
- Quantitative polymerase chain reaction (qPCR) for gene expression analysis.
- Transwell assays for cell invasion and enzyme-linked immunosorbent assay (ELISA) for cytokine levels.
Main Results:
- High glucose upregulated cGAS, STING, and downstream signaling proteins (IRF3, TBK1) in HMrSV5 cells.
- si-cGAS or RU.521 treatment suppressed cGAS-STING activation, MMT markers (α-SMA, Vimentin), cell invasion, and pro-inflammatory cytokines (IL-6, TNF-α).
Conclusions:
- The cGAS-STING pathway is activated by high glucose and promotes MMT in peritoneal mesothelial cells.
- Inhibiting the cGAS-STING pathway mitigates high glucose-induced peritoneal fibrosis.
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