S1PR3拮抗剂通过ROCK1-Drp1信号通路改善脓毒性急性肾损伤的内皮功能障碍

IF 3.7 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular immunology Pub Date : 2026-03-01 Epub Date: 2026-02-14 DOI:10.1016/j.molimm.2026.02.004

Zhipeng Xu , Jueyue Yan , Gan Luo , Qinghui Fu , Hanbin Wang , Jue Zhang , Xing Fang , Shaoyang Zhang , Baoli Cheng , Xiangming Fang

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引用次数: 0

摘要

目的磷素-1-磷酸受体3 （S1PR3）主要表达于内皮细胞，在炎症反应中起重要作用。然而，其在脓毒性急性肾损伤（S-AKI）发病机制中的作用仍不明确。本研究旨在阐明S1PR3在S-AKI期间内皮功能障碍中的作用及其潜在机制。方法采用腹腔注射脂多糖（LPS）诱导小鼠急性肾损伤。采用流式细胞术、埃文斯蓝染色法（EBD）和透射电镜（TEM）观察肾内皮功能和线粒体完整性。使用S1PR3拮抗剂TY-52156和脂质体制剂在人脐静脉内皮细胞（HUVECs）中进行了机制研究。结果LPS刺激后24 h，血清肌酐（SCr）、血尿素氮（BUN）和肾S1PR3表达显著升高，且S1PR3主要定位于内皮细胞。与S1pr3+ /+小鼠相比，S1pr3-/-小鼠肾功能改善，白细胞浸润减少，ATP生成增加。S1PR3激活与线粒体功能障碍、细胞骨架重塑和内皮通透性增加有关。在体外，TY-52156减少了线粒体Ca2+积累，恢复了ATP水平，并保留了细胞骨架组织和粘附体连接的完整性。为了提高溶解度和生物相容性，我们将TY-52156包封在带负电荷或中性电荷的脂质体中，其中lp - negy -TY-52156效果更佳。在体内，lp - negi - ty -52156减轻了S-AKI的内皮渗漏、线粒体损伤和肾功能障碍。结论内皮细胞S1PR3是S-AKI中线粒体功能障碍和屏障破坏的关键调节因子。脂质体递送S1PR3拮抗剂代表了一种有希望的治疗策略，以保持内皮完整性和减轻脓毒性肾损伤。

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S1PR3 antagonism ameliorates endothelial dysfunction in septic acute kidney injury through the ROCK1–Drp1 signalling pathway

Objective

Sphingosine-1-phosphate receptor 3 (S1PR3) is predominantly expressed in endothelial cells and plays important roles in inflammatory responses. However, its contribution to the pathogenesis of septic acute kidney injury (S-AKI) remains poorly defined. This study aimed to elucidate the role and underlying mechanisms of S1PR3 in endothelial dysfunction during S-AKI.

Methods

S-AKI was induced in mice by intraperitoneal lipopolysaccharide (LPS) injection. Renal endothelial function and mitochondrial integrity were assessed by flow cytometry, Evans blue dye (EBD) assays and transmission electron microscope (TEM). Mechanistic studies were conducted in human umbilical vein endothelial cells (HUVECs) using the S1PR3 antagonist TY-52156 and liposomal formulations.

Results

Serum creatinine (SCr), blood urea nitrogen (BUN) and renal S1PR3 expression were significantly increased 24 h after LPS challenge in wild-type mice, with S1PR3 predominantly localised to endothelial cells. Compared with S1pr3^+ /+ mice, S1pr3^-/- mice exhibited improved renal function, reduced leukocyte infiltration and enhanced ATP production. S1PR3 activation was associated with mitochondrial dysfunction, cytoskeletal remodelling and increased endothelial permeability. In vitro, TY-52156 reduced mitochondrial Ca²⁺ accumulation, restored ATP levels and preserved cytoskeletal organisation and adherens junction integrity. To improve solubility and biocompatibility, TY-52156 was encapsulated into negatively or neutrally charged liposomes, of which LP-Neg-TY-52156 showed superior efficacy. In vivo, LP-Neg-TY-52156 alleviated endothelial leakage, mitochondrial injury and renal dysfunction in S-AKI.

Conclusion

Endothelial S1PR3 is a key mediator of mitochondrial dysfunction and barrier disruption in S-AKI. Liposomal delivery of S1PR3 antagonists represents a promising therapeutic strategy for preserving endothelial integrity and attenuating septic renal injury.

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来源期刊

Molecular immunology 医学-免疫学

CiteScore

6.90

自引率

2.80%

发文量

324

审稿时长

50 days

期刊介绍： Molecular Immunology publishes original articles, reviews and commentaries on all areas of immunology, with a particular focus on description of cellular, biochemical or genetic mechanisms underlying immunological phenomena. Studies on all model organisms, from invertebrates to humans, are suitable. Examples include, but are not restricted to: Infection, autoimmunity, transplantation, immunodeficiencies, inflammation and tumor immunology Mechanisms of induction, regulation and termination of innate and adaptive immunity Intercellular communication, cooperation and regulation Intracellular mechanisms of immunity (endocytosis, protein trafficking, pathogen recognition, antigen presentation, etc) Mechanisms of action of the cells and molecules of the immune system Structural analysis Development of the immune system Comparative immunology and evolution of the immune system "Omics" studies and bioinformatics Vaccines, biotechnology and therapeutic manipulation of the immune system (therapeutic antibodies, cytokines, cellular therapies, etc) Technical developments.