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Title: [High STING expression exacerbates renal ischemia-reperfusion injury in mice by regulating the TLR4/NF-κB/NLRP3 pathway and promoting inflammation and apoptosis].
Author: Tao H, Luo J, Wen Z, Yu G, Su X, Wang X, Guan H, Chen Z.
Journal: Nan Fang Yi Ke Da Xue Xue Bao; 2024 Jul 20; 44(7):1345-1354. PubMed ID: 39051080.
Abstract:
OBJECTIVE: To investigate renal expression level of STING in mice with renal ischemia-reperfusion injury (IRI) and its regulatory role in IRI. METHODS: C57BL/6 mice were divided into sham operation group, IRI (induced by clamping the renal artery) model group, IRI+DMSO treatment group, and IRI+SN-011 treatment group. Serum creatinine and blood urea nitrogen of the mice were analyzed, and pathological changes in the renal tissue were assessed with PAS staining. RT-qPCR, ELISA, Western blotting, and immunohistochemistry were used to detect the expression levels of STING, KIM-1, Bcl-2, Bax, caspase-3, TLR4, P65, NLRP3, caspase-1, CD68, MPO, IL-1β, IL-6, and TNF-α in the renal tissues. In the cell experiment, HK-2 cells exposed to hypoxia-reoxygenation (H/R) were treated with DMSO or SN-011, and cellular STING expression levels and cell apoptosis were analyzed using RT-qPCR, Western blotting or flow cytometry. RESULTS: In C57BL/6 mice, renal IRI induced obvious renal tissue damage, elevation of serum creatinine and blood urea nitrogen levels and renal expression levels of KIM-1, STING, TLR4, P65, NLRP3, caspase-1, caspase-3, Bax, CD68, MPO, IL-1β, IL-6, and TNF-α, and reduction of Bcl-2 expression level. Treatment of the mouse models with SN-011 for inhibiting STING expression significantly alleviated these changes. In HK-2 cells, H/R exposure caused significant elevation of cellular STING expression and obviously increased cell apoptosis rate, which was significantly lowered by treatment with SN-011. CONCLUSION: Renal STING expression is elevated in mice with renal IRI to exacerbate renal injury by regulating the TLR4/NF-κB/NLRP3 pathway and promoting inflammation and apoptosis in the renal tissues. 目的: 探讨STING在肾缺血再灌注损伤（IRI）中的表达水平以及相关作用机制。方法: 在体内水平，将24只C57BL/6小鼠分为假手术组（Sham）、IRI组、IRI+药物溶剂组（IRI+DMSO）、IRI+SN-011组，6只/组。通过肾动脉夹闭方法建立IRI模型，通过血清肌酐和尿素氮检测、PAS染色检测肾组织损伤变化，采用RT-qPCR、ELISA、Western blotting和IHC法检测肾组织中STING、KIM-1、Bcl-2、Bax、caspase-3、TLR4、P65、NLRP3、caspase-1、CD68、MPO、 IL-1β、IL-6、TNF-α的水平。在体外水平，将HK-2细胞分为对照组、缺氧复氧（H/R）组、H/R+药物溶剂组（H/R+DMSO）、H/R+SN-011组，用厌氧包模拟缺氧环境，RT-qPCR和Western blotting法检测STING表达水平，流式细胞术检测各组细胞凋亡率。结果: 在体内水平，与Sham组相比，IRI组的PAS染色显示组织损伤增加（P<0.05），小鼠血清肌酐、尿素氮含量以及组织KIM-1、STING、TLR4、P65、NLRP3、caspase-1、caspase-3、Bax、CD68、MPO、IL-1β、IL-6、TNF-α表达水平升高（P<0.05），Bcl-2水平降低（P<0.05），SN-011抑制STING表达后，逆转了上述结果（P<0.05）。在体外水平，与对照组相比，H/R组STING的mRNA与蛋白水平升高（P<0.05），流式细胞仪检测显示细胞凋亡率上升（P<0.05），SN-011抑制STING表达，细胞凋亡率下降（P<0.05）。结论: STING在肾脏IRI中表达水平上升，且可通过作用于TLR4/NF-κB/NLRP3通路以及影响炎症与凋亡水平促进肾损伤。

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