α-乳香酸通过抑制TLR4介导的炎症通路改善急性肾损伤

doi:10.5246/jcps.2023.07.045

中国药学(英文版) ›› 2023, Vol. 32 ›› Issue (7): 539-550.DOI: 10.5246/jcps.2023.07.045

α-乳香酸通过抑制TLR4介导的炎症通路改善急性肾损伤

王番^#, 李锐莉^#, 王文军^#, 周晓燕^#, 刘美佑, 赵瑾怡, 文爱东, 王婧雯^*(), 贾艳艳^*()

空军军医大学西京医院药剂科, 陕西西安 710032

收稿日期:2022-11-17 修回日期:2022-12-21 接受日期:2023-03-09 出版日期:2023-07-31 发布日期:2023-07-31
通讯作者: 王婧雯, 贾艳艳
作者简介:
+ Tel.: +86-29-84771794, E-mail: 25961754@qq.com
+ E-mail: wangjingwen8021@163.com
基金资助:
The National Natural Science Foundation of China (Grant No. 81703795); the Traditional Chinese Medicine Research Project of Shaanxi Province Traditional Chinese Medicine Administration (Grant No. JCMS050); the Shaanxi Province Natural Science Basic Research Project (Grant No. 2018JQ8065); and the Shaanxi Provincial Key R&D Program Project (Grant No. 2020ZDLSF03-09).

α-Boswellic acid ameliorates acute kidney injury by inhibiting the TLR4-mediated inflammatory pathway

Fan Wang^#, Ruili Li^#, Wenjun Wang^#, Xiaoyan Zhou^#, Meiyou Liu, Jinyi Zhao, Aidong Wen, Jingwen Wang^*(), Yanyan Jia^*()

Xijing Hospital, Medical University of the Air Force, Department of Pharmacy, 710032, Xi’an, Shaanxi, China

Received:2022-11-17 Revised:2022-12-21 Accepted:2023-03-09 Online:2023-07-31 Published:2023-07-31
Contact: Jingwen Wang, Yanyan Jia
About author:
# These authors contributed equally to this study.

摘要/Abstract

摘要：

α-乳香酸(α-BA)是乳香药材经过提取、分离、纯化后的产物, 可用于治疗多种炎症性疾病。本研究旨在通过体内外实验评估α-BA在改善缺血再灌注损伤诱导的急性肾损伤中的作用。对大鼠进行右肾切除和左肾缺血再灌注损伤, 损伤前0.5 h给予α-BA处理。体内实验, 对组织进行肾功能、组织病理学和TUNEL染色分析。体外实验, 对近端肾小管细胞(HK-2)进行氧糖剥夺(OGD)操作, 以模仿缺血再灌注损伤, 并检测细胞存活率、免疫荧光染色及Toll样受体4(TLR4)和核因子(NF)-κB表达。结果显示, 给予α-BA的模型组大鼠血清肌酐和血尿素氮水平显著降低, 并缓解细胞凋亡和肾脏形态学改变; 经α-BA处理的HK-2细胞, NF-κBp6的表达明显降低。表明α-BA改善缺血再灌注损伤诱导的急性肾损伤, 部分原因是通过TLR4介导的炎症通路促进肾小管细胞存活, 从而改善肾功能。

关键词: 急性肾损伤, 缺血再灌注损伤, 炎症, 凋亡, α-乳香酸

Abstract:

α-Boswellic acid (α-BA) is a bioactive compound derived from the resin of the African myrrh tree, which has been shown to have therapeutic potential for a range of inflammatory disorders. In the present study, we aimed to evaluate the effects of α-BA on improving ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI), both in vivo and in vitro. In this experiment, rats that underwent right nephrectomy and left kidney IRI were administered with α-BA 30 min before IRI. The rats’ renal function was evaluated, and their kidney tissues were subjected to histopathological analysis and TUNEL staining. For in vitro evaluation, the proximal renal tubular cells (HK-2) were subjected to oxygen-glucose deprivation (OGD). Cell viability, immunofluorescence staining, and Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB expressions were investigated. After treatment with α-BA, the levels of serum creatinine and blood urea nitrogen were significantly reduced in the rats subjected to IRI, and apoptosis was alleviated, along with improvements in renal morphological changes. Moreover, the treatment of HK-2 cells with α-BA effectively reduced the expression of NF-κB p65. Collectively, the results suggested that α-BA improved IRI-induced AKI in part by promoting the survival of renal tubular cells through the TLR4-mediated inflammatory pathway, thereby improving renal function.

Key words: Acute kidney injury, Ischemia reperfusion injury, Inflammation, Apoptosis, α-Boswellic acid

Supporting:

王番, 李锐莉, 王文军, 周晓燕, 刘美佑, 赵瑾怡, 文爱东, 王婧雯, 贾艳艳. α-乳香酸通过抑制TLR4介导的炎症通路改善急性肾损伤[J]. 中国药学(英文版), 2023, 32(7): 539-550.

Fan Wang, Ruili Li, Wenjun Wang, Xiaoyan Zhou, Meiyou Liu, Jinyi Zhao, Aidong Wen, Jingwen Wang, Yanyan Jia. α-Boswellic acid ameliorates acute kidney injury by inhibiting the TLR4-mediated inflammatory pathway[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(7): 539-550.

图/表 6

Figure 1. Effect of α-BA on kidney function tests in IRI-induced AKI in rats. (A) Chemical structure of α-BA. (B, C) Increases in BUN and Scr levels at 24 h after IRI were abrogated by α-BA of different concentrations (n = 8 rats/group). *P < 0.05 vs. Sham; #P < 0.05 vs. IRI.

Figure 2. Effect of α-BA on kidney injury after IR administration. (A) Representative photomicrographs (H&E staining; magnification, 200×) of renal sections from rats under various experimental conditions. (B) Assessment of tubular injury.*P < 0.05 vs. Sham; #P < 0.05 vs. IRI.

Figure 3. α-BA pretreatment ameliorates tubular apoptosis induced by IRI in vivo. (A) Representative images (magnification, ×400) of renal TUNEL assay from rats subjected to sham, IRI, and IRI + α-BA. (B) The percentage of TUNEL-positive cells in kidney sections was increased following IRI and decreased following treatment with α-BA. *P < 0.05 vs. Sham; #P < 0.05 vs. IRI, n = 8.

Figure 4. α-BA pretreatment ameliorates tubular apoptosis induced by IRI in vitro. (A) Anti-apoptotic effects on HK-2 cells following OGD injury were confirmed by Hoechst 33258 staining. A quantitative analysis of apoptosis is shown in (B). Data were presented as mean ± SD and represented three independent experiments; *P < 0.05 vs. control; #P < 0.05 vs. OGD. (C) The effect of α-BA on HK-2 cell viability was tested by MTT assay. Cells in the sham group were considered 100% viable. Data were presented as mean ± SD (n = 3). *P < 0.05 vs. Sham; #P < 0.05 vs. OGD.

Figure 5. Effects of α-BA on activation of the TLR4 and NF-κB signaling pathway in IRI-induced AKI. Representative Western blots showing the effects of α-BA on TLR4 and NF-κB expression in the kidney after 40 min of ischemia followed by 24 h of reperfusion. α-Tubulin was used to show equal amounts of protein loading in each lane. (A) Representative Western blots showing the effects of α-BA on TLR4 and NF-κB p65 expression. (B) Relative band densities of TLR4 and (C) NF-κB p65 to the mean value of the control. *P < 0.05 vs. Sham; #P < 0.05 vs. IRI.

Figure 6. Effect of α-BA on TLR4 and NF-κB signaling pathway in OGD-induced HK-2 cells. HK-2 cells were incubated in the presence or absence of different concentrations of α-BA (10, 20, and 40 μM) for 24 h and then incubated with or without OGD for another 24 h. α-Tubulin was used to show equal amounts of protein loading in each lane. (A) The expression levels of TLR4 and NF-κB p65 in cell lysates were determined by Western blotting analysis. (B) Relative band densities of TLR4 and (C) NF-κB p65 to the mean value of the control. All data were presented as mean ± SD from three separate experiments. *P < 0.05 vs. Control; #P < 0.05 vs. OGD.

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α-乳香酸通过抑制TLR4介导的炎症通路改善急性肾损伤

α-Boswellic acid ameliorates acute kidney injury by inhibiting the TLR4-mediated inflammatory pathway

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