Gao Xianli, Guo Caiyun, Li Wenjun, Deng Yingdong, Ning Wenjun, Xie Jiaqi, Zhan Xiaoying, Fan Youling, Chen Hongtao, Huang Zengping, Zhou Jun
Department of Anesthesiology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Department of Anesthesiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China.
Chin Med. 2024 Jan 16;19(1):11. doi: 10.1186/s13020-024-00885-2.
The role of pyroptosis in kidney disease is limited and incomplete. Quercetin, a flavonoid compound present in a variety of fruits, vegetables, and plants, has shown antioxidant and anti-inflammatory properties. This study was designed to validate the importance of pyroptosis in an experimental model of folic acid nephropathy and to explore the effect of quercetin in protecting against pyroptosis.
Gene set enrichment analysis (GSEA) and weighted gene co-expression network analysis (WGCNA) were used to establish the correlation between pyroptosis and folic acid nephropathy. Immune cell infiltration, network pharmacology and single-cell RNA sequencing analysis were utilized to ascertain the specific target of quercetin in relation to pyroptosis. Finally, quercetin's role was verified in vivo and in vitro.
The GSEA analysis revealed a significant correlation between pyroptosis and folic acid nephropathy (NES = 1.764, P = 0.004). The hub genes identified through WGCNA were closely associated with inflammation. Molecular docking demonstrated a strong binding affinity between quercetin and caspase-1, a protein known to be involved in macrophage function, as confirmed by immune cell infiltration and single-cell analysis. Quercetin demonstrated a significant amelioration of kidney injury and reduction in macrophage infiltration in the animal model. Furthermore, quercetin exhibited a significant inhibition of caspase-1 expression, subsequently leading to the inhibition of pro-inflammatory cytokines expression, such as IL-1β, IL-18, TNF-α, and IL-6. The inhibitory effect of quercetin on macrophage pyroptosis was also confirmed in RAW264.7 cells.
This study contributes substantial evidence to support the significant role of pyroptosis in the development of folic acid nephropathy, and highlights the ability of quercetin to downregulate caspase-1 in macrophages as a protective mechanism against pyroptosis.
细胞焦亡在肾脏疾病中的作用有限且不完整。槲皮素是一种存在于多种水果、蔬菜和植物中的黄酮类化合物，已显示出抗氧化和抗炎特性。本研究旨在验证细胞焦亡在叶酸肾病实验模型中的重要性，并探讨槲皮素对预防细胞焦亡的作用。
采用基因集富集分析（GSEA）和加权基因共表达网络分析（WGCNA）来建立细胞焦亡与叶酸肾病之间的相关性。利用免疫细胞浸润、网络药理学和单细胞RNA测序分析来确定槲皮素与细胞焦亡相关的具体靶点。最后，在体内和体外验证了槲皮素的作用。
GSEA分析显示细胞焦亡与叶酸肾病之间存在显著相关性（标准化富集分数[NES]=1.764，P=0.004）。通过WGCNA鉴定的枢纽基因与炎症密切相关。分子对接表明槲皮素与半胱天冬酶-1具有很强的结合亲和力，免疫细胞浸润和单细胞分析证实半胱天冬酶-1是一种已知参与巨噬细胞功能的蛋白质。在动物模型中，槲皮素显著改善了肾脏损伤并减少了巨噬细胞浸润。此外，槲皮素显著抑制了半胱天冬酶-1的表达，随后导致促炎细胞因子如白细胞介素-1β、白细胞介素-18、肿瘤坏死因子-α和白细胞介素-6的表达受到抑制。槲皮素对RAW264.7细胞中巨噬细胞焦亡的抑制作用也得到了证实。
本研究提供了大量证据支持细胞焦亡在叶酸肾病发生发展中的重要作用，并强调了槲皮素下调巨噬细胞中半胱天冬酶-1的能力作为一种针对细胞焦亡的保护机制。
