昆布岩藻聚糖通过抑制 NF-κB 通路保护肾小管上皮细胞免受尿酸诱导的 NLRP3 介导的焦亡。

Fucoidan from Laminaria japonica protects renal tubular epithelial cells from uric acid induced NLRP3-mediated pyroptosis through inhibition of NF-κB pathway.

机构信息

College of Chemistry & Environmental Science, Guangdong Ocean University, Zhanjiang, 524088, China.

出版信息

J Ethnopharmacol. 2024 Dec 5;335:118614. doi: 10.1016/j.jep.2024.118614. Epub 2024 Jul 23.

DOI:10.1016/j.jep.2024.118614

PMID:39053708

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Hyperuricemia is a common metabolic disease with prominent morbidity, it can lead to many adverse effects and complications, such as chronic nephrosis. Fucoidan has been used as natural drug for acute and chronic kidney disease for over 20 years in China, but the precise mechanisms underlying the renal protective function are still indefinable.

PURPOSE

This study is conducted to explore alleviation of fucoidan (FPS) from Laminaria japonica on urate-induced NOD-like receptor family, pyrin domain-containing 3 (NLRP3)-mediated pyroptosis in renal tubular epithelial cells HK-2, as well as the mechanism of nuclear factor κB (NF-κB) signaling pathway involved.

MATERIALS AND METHODS

HK-2 cells were treated with FPS, uric acid (UA), and inhibitor of NF-κB signaling pathway. Nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity were determined with detection kits. Activation of intercellular NLRP3 inflammasome and NF-κB signaling pathway, gasdermin D (GSDMD) expression level were evaluated with Western blot and quantitative reverse transcription-PCR (qRT-PCR), and immunofluorescent analysis.

RESULTS

Data showed that UA induced cellular inflammatory response demonstrated by elevated NO content, iNOS activity and expression level of NLRP3 inflammasome-mediated pyroptosis associated molecules including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), Caspase-1, interleukin 18 (IL-18) and GSDMD, moreover the NF-κB signaling pathway was activated by UA. However, FPS exposure inhibited efficiently the UA induced adverse effect.

CONCLUSION

It can be concluded that FPS inhibited UA-induced NLRP3-mediated pyroptosis in HK-2 cells through repressing NF-κB signaling pathway.

摘要

民族药理学相关性

高尿酸血症是一种常见的代谢性疾病，发病率较高，可导致许多不良后果和并发症，如慢性肾病。在中国，褐藻糖胶已被用作治疗急、慢性肾病的天然药物超过 20 年，但确切的肾脏保护作用机制仍未明确。

目的

本研究旨在探讨来自裙带菜的褐藻糖胶（FPS）对尿酸诱导的 NOD 样受体家族、含pyrin 结构域的蛋白 3（NLRP3）介导的肾小管上皮细胞 HK-2 细胞 pyroptosis 的缓解作用，以及涉及的核因子 kappa B（NF-κB）信号通路的机制。

材料和方法

用 FPS、尿酸（UA）和 NF-κB 信号通路抑制剂处理 HK-2 细胞。用检测试剂盒测定一氧化氮（NO）含量和诱导型一氧化氮合酶（iNOS）活性。用 Western blot 和定量逆转录 PCR（qRT-PCR）及免疫荧光分析评估细胞间 NLRP3 炎性小体和 NF-κB 信号通路的激活以及 GSDMD 的表达水平。

结果

数据表明，UA 诱导的细胞炎症反应表现为 NO 含量、iNOS 活性和 NLRP3 炎性小体介导的细胞焦亡相关分子（包括 NLRP3、凋亡相关斑点样蛋白含有半胱氨酸天冬氨酸酶募集域（ASC）、Caspase-1、白细胞介素 18（IL-18）和 GSDMD）的表达水平升高，此外，UA 还激活了 NF-κB 信号通路。然而，FPS 暴露能有效地抑制 UA 诱导的不良反应。