Deficiency of lysophosphatidic acid receptor 3 decreases erythropoietin production in hypoxic mouse kidneys.

IF 3.9 2区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Lipids in Health and Disease Pub Date : 2024-11-18 DOI:10.1186/s12944-024-02367-8

Nan Yin, Xuyuan Li, Di Zhang, Mengxia Qu, Shengqiang Pei, Xi Chen, Xiaotian Zhang, Junjie Zhang

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引用次数: 0

Abstract

Background: Lysophosphatidic acid (LPA) is a lipid mediator with diverse biological functions through its receptors on the cell membrane. As one of the six LPA receptors, LPA receptor 3 (LPAR3) is highly expressed in mouse kidneys, but its physiological function in the kidney has been poorly explored.

Methods: Wild-type (WT) and Lpar3^-/- mice were used to investigate the renal physiological function of LPAR3 under hypoxia. The expression levels of LPA receptors in the kidneys of WT mice with or without exposure to hypoxia (8% O₂) were detected by RT‒qPCR. RNA sequencing analysis was performed to identify differences in gene expression profiles between the hypoxic kidneys of WT and Lpar3^-/- mice. The effects of LPAR3 deficiency and treatment with the LPAR1/3 inhibitor Ki16425 or the LPAR3 selective agonist 2S-OMPT on erythropoietin (EPO) production in the kidneys of hypoxic mice were determined by RT‒qPCR and ELISAs. The mechanism of LPAR3-mediated regulation of EPO expression was further studied in vivo with mouse models and in vitro with cultured human cells.

Results: LPAR3 is the major LPA receptor in mouse kidneys, and its expression is significantly upregulated under hypoxic conditions. RNA sequencing analysis revealed that, compared with WT mice, Lpar3^-/- mice presented a significant decrease in hypoxia-induced EPO expression in the kidney, together with reduced plasma EPO levels and lower hematocrit and hemoglobin levels. Hypoxic renal EPO expression in WT mice was diminished by the administration of the LPAR1/3 inhibitor Ki16425 and increased by 2S-OMPT, a selective agonist of LPAR3. Hypoxia-induced HIF-2α accumulation in mouse kidneys was impaired by LPAR3 deficiency. Further studies revealed that the PI3K/Akt pathway participated in the regulation of HIF-2α accumulation and EPO expression by LPAR3 under hypoxic conditions.

Conclusions: Our study revealed the role of LPAR3 in promoting the HIF-2α‒EPO axis in hypoxic mouse kidneys, suggesting that the LPA receptor may serve as a novel potential pharmaceutical target to regulate renal EPO production in hypoxia-related situations, such as chronic kidney disease and altitude disease.

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溶血磷脂酸受体 3 的缺乏会降低缺氧小鼠肾脏的促红细胞生成素分泌。

背景：溶血磷脂酸（LPA）是一种脂质介质，它通过细胞膜上的受体发挥多种生物学功能。作为六种 LPA 受体之一，LPA 受体 3（LPAR3）在小鼠肾脏中高表达，但其在肾脏中的生理功能却鲜有研究：方法：采用野生型（WT）和Lpar3-/-小鼠研究LPAR3在缺氧条件下的肾脏生理功能。方法：用 RT-qPCR 技术检测缺氧（8% O2）条件下野生型小鼠和 Lpar3-/- 小鼠肾脏中 LPA 受体的表达水平。进行了 RNA 测序分析，以确定 WT 小鼠和 Lpar3-/- 小鼠缺氧肾脏基因表达谱的差异。通过RT-qPCR和ELISA测定了LPAR3缺乏和LPAR1/3抑制剂Ki16425或LPAR3选择性激动剂2S-OMPT治疗对缺氧小鼠肾脏促红细胞生成素（EPO）产生的影响。通过小鼠模型和体外培养的人体细胞，进一步研究了 LPAR3 介导的 EPO 表达调控机制：结果：LPAR3是小鼠肾脏中主要的LPA受体，其表达在缺氧条件下显著上调。RNA测序分析表明，与WT小鼠相比，Lpar3-/-小鼠肾脏中缺氧诱导的EPO表达明显减少，同时血浆EPO水平降低，血细胞比容和血红蛋白水平降低。服用 LPAR1/3 抑制剂 Ki16425 可减少 WT 小鼠肾脏缺氧 EPO 的表达，而 LPAR3 的选择性激动剂 2S-OMPT 则可增加肾脏缺氧 EPO 的表达。缺氧诱导的HIF-2α在小鼠肾脏中的积累因LPAR3缺乏而受损。进一步研究发现，在缺氧条件下，PI3K/Akt通路参与了LPAR3对HIF-2α积累和EPO表达的调控：结论：我们的研究揭示了LPAR3在缺氧小鼠肾脏中促进HIF-2α-EPO轴的作用，这表明LPA受体可作为一种新的潜在药物靶点，在慢性肾病和高原病等缺氧相关情况下调节肾脏EPO的产生。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Lipids in Health and Disease 生物-生化与分子生物学

CiteScore

7.70

自引率

2.20%

发文量

122

审稿时长

3-8 weeks

期刊介绍： Lipids in Health and Disease is an open access, peer-reviewed, journal that publishes articles on all aspects of lipids: their biochemistry, pharmacology, toxicology, role in health and disease, and the synthesis of new lipid compounds. Lipids in Health and Disease is aimed at all scientists, health professionals and physicians interested in the area of lipids. Lipids are defined here in their broadest sense, to include: cholesterol, essential fatty acids, saturated fatty acids, phospholipids, inositol lipids, second messenger lipids, enzymes and synthetic machinery that is involved in the metabolism of various lipids in the cells and tissues, and also various aspects of lipid transport, etc. In addition, the journal also publishes research that investigates and defines the role of lipids in various physiological processes, pathology and disease. In particular, the journal aims to bridge the gap between the bench and the clinic by publishing articles that are particularly relevant to human diseases and the role of lipids in the management of various diseases.