灵桂柱肝汤通过TLR4/NF-KB/IRE1α通路改善心力衰竭继发性肾损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-18 DOI:10.1016/j.phymed.2025.156862

Jiayu Lv , Zhenyue Fu , Yuxin Wang , Chunmei Chen , Yajiao Wang , Bingxuan Zhang , Huaqin Wu , Qingqiao Song , Yumeng Li

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引用次数: 0

摘要

慢性心力衰竭（CHF）和慢性肾脏疾病（CKD）相互促进彼此的发生和进展。心力衰竭引起的肾损伤目前缺乏有效的治疗方法。既往研究表明，灵桂竹肝汤（LGZGD）可显著改善心力衰竭（HF）和心脏重构，并有肾保护作用的报道。然而，LGZGD在心力衰竭肾损伤中的作用和机制尚不清楚。目的在此基础上，探讨LGZGD对HF继发性肾损伤的影响及其机制。研究设计采用网络药理学方法预测LGZGD治疗心肾综合征（CRS）的潜在靶点。采用单次腹腔注射单苦参碱（MCT）建立右心衰伴静脉充血的CRS体内模型。以TNF-α刺激的NRK52E细胞作为体外模型。我们通过体内和体外实验验证了LGZGD的作用。此外，与先前鉴定的LGZGD组分进行分子对接，以预测潜在的作用靶点。结果slggzgd能明显改善CRS大鼠的心脏和肾脏功能，改善肾组织病理学改变。抑制肾脏TLR4/NF-κB/IRE1α通路，下调焦热相关蛋白（NLRP3、GSDMD、Caspase-1、IL-18、IL-1β）的表达。含有lgzgd的血清和TLR4抑制剂（TAK-242）均能显著降低TNF-α刺激的NRK52E细胞的凋亡，并降低TLR4/NF-κB/IRE1α通路信号和热解相关蛋白的水平。分子对接表明，neoliquiritin （CID_51666248）、enoxolon （CID_10114）和liquiritin （CID_503737）能够稳定结合IRE1α、caspase-1和NF-κB等关键靶点。结论本研究首次证实LGZGD可能通过TLR4/NF-κB/IRE1α通路改善HF继发性肾损伤，为今后CRS治疗的研究提供有价值的见解。

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Lingguizhugan decoction ameliorates renal injury secondary to heart failure by improving pyroptosis through TLR4/NF-KB/IRE1α pathway

Background

Chronic heart failure (CHF) and chronic kidney disease (CKD) mutually promote the onset and progression of each other. Renal injury caused by heart failure currently lacks effective treatments. Previous studies have shown that Linggui Zhugan decoction (LGZGD) can significantly improve heart failure (HF) and cardiac remodeling, and has been reported to have renal protective effects. However, the effects and mechanisms of LGZGD in heart failure-induced renal injury remain unclear.

Purpose

Based on these findings, this study aims to investigate the effects and underlying mechanisms of LGZGD on renal injury secondary to HF.

Study Design

We used network pharmacology to predict potential targets of LGZGD in the treatment of cardiorenal syndrome (CRS). An in vivo model of CRS with right heart failure and venous congestion was established by a single intraperitoneal injection of monocrotaline (MCT). TNF-α-stimulated NRK52E cells were used as an in vitro model. We validated the effects of LGZGD in both in vivo and in vitro experiments,. Additionally, molecular docking with the components of LGZGD identified previously was performed to predict potential targets of action.

Results

LGZGD significantly improved heart and kidney function as well as renal histopathological changes in CRS rats. It inhibited the TLR4/NF-κB/IRE1α pathway in the kidneys and downregulated the expression of pyroptosis-related proteins (NLRP3, GSDMD, Caspase-1, IL-18, and IL-1β). Both LGZGD-containing serum and the TLR4 inhibitor (TAK-242) significantly reduced apoptosis in TNF-α-stimulated NRK52E cells and decreased the levels of TLR4/NF-κB/IRE1α pathway signaling and pyroptosis-related proteins. Molecular docking suggested that neoliquiritin (CID_51666248), enoxolon (CID_10114), and liquiritin (CID_503737) could stably bind to key targets such as IRE1α, caspase-1, and NF-κB.

Conclusion

This study demonstrated for the first time that LGZGD might ameliorate renal injury secondary to HF by improving pyroptosis through the TLR4/NF-κB/IRE1α pathway, which may provide valuable insights for future research in the treatment of CRS.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.