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希佩尔-林道肿瘤抑制基因突变调控铁死亡炎症通路中脂联素 2 的表达。

The von Hippel-Lindau Tumor Suppressor Gene Mutations Modulate Lipocalin-2 Expression in Ferroptotic-Inflammatory Pathways.

机构信息

Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan.

Department of Nursing, Cardinal Tien College of Healthcare and Management, New Taipei City 231, Taiwan.

出版信息

Oxid Med Cell Longev. 2023 Jan 21;2023:7736638. doi: 10.1155/2023/7736638. eCollection 2023.

DOI:10.1155/2023/7736638
PMID:36718277
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9884170/
Abstract

A previous study of an animal model with tumor suppressor gene von Hippel-Lindau (VHL) conditional knockdown suggested that tissue inflammation and fibrosis play important roles in the development of clear-cell renal cell carcinoma (ccRCC), which is consistent with the epidemiological evidence linking inflammatory kidney disease and renal cancer. Ferroptosis and inflammation have been linked in a recent study, but the exact mechanism remains unclear. This study is aimed at investigating the mechanism of lipocalin-2- (LCN-2-) mediated ferroptosis and inflammation in -mutated HK-2 cells and mouse primary proximal tubule cells (mRTCs) and the polarization of macrophage RAW 264.7 cells. Based on the levels of lipid reactive oxygen species (ROS) and the expression of glutathione peroxidase 4 (GPX4) in HK-2 cells, we observed that a VHL mutation increased ROS production and depressed GPX4 expression, whereas LCN-2 knockdown reversed these effects. Accordingly, VHL appears to affect ferroptosis in an LCN-2-dependent manner. We also revealed that LCN-2 sensitizes HK-2 cells to inflammation and macrophage RAW 264.7 cells to M1-like polarization. This study provides novel insights into the potential therapeutic target and strategy for attenuating the progression of ccRCC by revealing the role of VHL in regulating chronic inflammation within the LCN-2-ferroptosis pathway.

摘要

先前的一项动物模型研究表明，肿瘤抑制基因 von Hippel-Lindau (VHL) 条件性敲低会导致组织炎症和纤维化，这与炎症性肾病和肾癌之间的流行病学证据一致。最近的一项研究表明铁死亡和炎症之间存在关联，但确切的机制尚不清楚。本研究旨在探讨 LCN-2 介导的突变型 HK-2 细胞和小鼠原代近端肾小管细胞 (mRTC) 中铁死亡和炎症以及 RAW 264.7 细胞极化的机制。基于 HK-2 细胞中脂质活性氧 (ROS) 的水平和谷胱甘肽过氧化物酶 4 (GPX4) 的表达，我们观察到 VHL 突变增加了 ROS 的产生并抑制了 GPX4 的表达，而 LCN-2 敲低则逆转了这些效应。因此，VHL 似乎以 LCN-2 依赖的方式影响铁死亡。我们还揭示了 LCN-2 使 HK-2 细胞易发生炎症，使 RAW 264.7 细胞向 M1 样极化。本研究通过揭示 VHL 在调节 LCN-2-铁死亡途径中的慢性炎症中的作用，为通过抑制铁死亡和炎症反应来减轻 ccRCC 进展提供了新的潜在治疗靶点和策略。

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Lipocalin-2 silencing suppresses inflammation and oxidative stress of acute respiratory distress syndrome by ferroptosis via inhibition of MAPK/ERK pathway in neonatal mice.脂联素-2 沉默通过抑制 MAPK/ERK 通路抑制新生鼠急性呼吸窘迫综合征的铁死亡，从而抑制炎症和氧化应激。
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