血管生成素样蛋白4通过整合素β5/黏着斑激酶信号通路加重急性肾损伤中的肾小管上皮细胞焦亡。
Angiopoietin-like 4 exacerbates renal tubular epithelial cell pyroptosis in acute kidney injury via integrin β5/FAK signaling pathway.
作者信息
Shen Xiujin, Wang Haibing, Weng Chunhua, He Yongchun, Shao Xue, Le Jingyun, Chen Hui, Shen Qixia, Chen Jianghua, Jiang Hong
机构信息
Kidney Disease Center, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Zhejiang University, Hangzhou, Zhejiang, China.
Central Laboratory, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
出版信息
Kidney Int. 2025 Aug 22. doi: 10.1016/j.kint.2025.07.025.
INTRODUCTION
Angiopoietin-like 4 (Angptl4) is a secreted protein that participates in multiple biological processes. Our previous study on the effect of Angptl4 in minimal change disease (MCD) unexpectedly indicated a close correlation between Angptl4 and kidney function, especially in MCD patients combined with AKI, implying a possible function of Angptl4 in AKI. However, the role and molecular mechanism of Angptl4 in AKI are undetermined.
METHODS
Biopsy tissue and serum of patients with AKI were analyzed by ELISA and immunohistochemistry to evaluate ANGPTL4 expression and its correlation with kidney function. For in vitro study, ANGPTL4 overexpressed and knocked down HK-2 cells were used to determine the effect of ANGPTL4 on cell pyroptosis. For in vivo study, Angptl4 global and conditional knockout mice were generated to study AKI using cisplatin- or ischemia/reperfusion-induced AKI mouse models. Additionally, we used various experimental approaches to investigate how ANGPTL4 induces tubular cell injury via interaction with integrin β.
RESULTS
Angptl4 was up regulated in kidney tubular epithelial cells of multiple AKI models and correlated with kidney function. ANGPTL4 aggravated tumor suppressor GSDME-dependent cell pyroptosis in vitro. In genetic mice, overexpression of Angptl4 worsened kidney function, inflammation, and cell pyroptosis, whereas ablation of Angptl4 attenuated kidney injury in AKI. Mechanistically, ANGPTL4 interacted with integrin β5 and activated focal adhesion kinase (FAK), promoting kidney tubular pyroptosis through the caspase 3/GSDME signaling pathway. Inhibition of integrin β5 or FAK alleviated kidney tubular pyroptosis and kidney dysfunction. Moreover, ANGPTL4 promoted the secretion of cytokines MCP-1 and RANTES by kidney tubular epithelial cells, enhancing macrophage recruitment.
CONCLUSIONS
Our results reveal that Angptl4 triggers pyroptosis and worsened kidney injury in AKI and offers a potential target for the diagnosis and treatment of AKI.
引言
血管生成素样4（Angptl4）是一种参与多种生物学过程的分泌蛋白。我们之前关于Angptl4在微小病变肾病（MCD）中作用的研究意外地表明，Angptl4与肾功能密切相关，尤其是在合并急性肾损伤（AKI）的MCD患者中，这意味着Angptl4在AKI中可能具有某种功能。然而，Angptl4在AKI中的作用和分子机制尚未明确。
方法
采用酶联免疫吸附测定（ELISA）和免疫组织化学方法分析AKI患者的活检组织和血清，以评估ANGPTL4的表达及其与肾功能的相关性。在体外研究中，使用过表达和敲低ANGPTL4的HK - 2细胞来确定ANGPTL4对细胞焦亡的影响。在体内研究中，构建Angptl4全身和条件性敲除小鼠，使用顺铂或缺血/再灌注诱导的AKI小鼠模型来研究AKI。此外，我们采用多种实验方法来研究ANGPTL4如何通过与整合素β相互作用诱导肾小管细胞损伤。
结果
在多种AKI模型的肾小管上皮细胞中，Angptl4表达上调且与肾功能相关。ANGPTL4在体外加重了肿瘤抑制因子GSDME依赖性细胞焦亡。在基因小鼠中，Angptl4过表达会使肾功能、炎症和细胞焦亡恶化，而敲除Angptl4则可减轻AKI中的肾损伤。机制上，ANGPTL4与整合素β5相互作用并激活粘着斑激酶（FAK），通过半胱天冬酶3/GSDME信号通路促进肾小管焦亡。抑制整合素β5或FAK可减轻肾小管焦亡和肾功能障碍。此外，ANGPTL4促进肾小管上皮细胞分泌细胞因子MCP - 1和RANTES，增强巨噬细胞募集。
结论
我们的研究结果表明，Angptl4在AKI中引发焦亡并加重肾损伤，为AKI的诊断和治疗提供了一个潜在靶点。
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