解开可溶性肾素受体介导的内皮功能障碍。

IF 4.2 3区医学 Q1 PHARMACOLOGY & PHARMACY

European journal of pharmacology Pub Date : 2025-04-03 DOI:10.1016/j.ejphar.2025.177601

Lachlan G. Schofield , Juyi Zhao , Yu Wang , Sarah J. Delforce , Saije K. Endacott , Eugenie R. Lumbers , Dan Ma , Kirsty G. Pringle

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引用次数: 0

摘要

背景：子痫前期以母体内皮功能障碍和新发高血压为特征。子痫前期妊娠母体可溶性prorenin受体（s(P)RR）水平升高，既往研究表明重组s(P)RR可引起高血压和血管功能障碍。本研究旨在探讨PRO20和s(P)RR拮抗剂对s(P)RR诱导的内皮功能障碍的影响及其与血管紧张素II型1受体（AT1R）的相互作用。方法：用100nM s(P)RR、10nM PRO20、10μM Losartan （AT1R拮抗剂）、10μM Aliskerin（肾素抑制剂）分别对人子宫微血管内皮细胞（HUtMECs）进行处理。PRO20预防子痫前期患者血清诱导的内皮功能障碍的能力也被评估。采用免疫印迹、qPCR和ELISA检测内皮功能障碍标志物。在AT1R机制研究中，在暴露于s(P)RR之前，使用对照或AT1R siRNA处理HUtMECs。通过AlphaFold-2预测AT1R和s(P)RR蛋白结构，并使用Schrödinger进行对接检测。结果：PRO20减轻了s(P)RR诱导的内皮功能障碍标志物内皮素-1、VCAM-1和ICAM-1 mRNA表达的升高，抑制了s(P)RR和子痫前期血清诱导的内皮素-1和VCAM-1蛋白表达的升高。Aliskerin对s(P) rr诱导的内皮功能障碍无影响。氯沙坦和AT1R siRNA能够分别阻止s(P)RR诱导的VCAM-1蛋白水平和ET-1 mRNA表达的增加。模型表明PRO20可以抑制s(P)RR-AT1R复合物的形成。结论：s(P)RR升高至少部分通过AT1R诱导内皮功能障碍。PRO20可以阻止s(P)RR-AT1R的形成，提示它可能是子痫前期和需要肾素-血管紧张素系统抑制的疾病的有效治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Unravelling soluble (pro)renin receptor-mediated endothelial dysfunction

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Unravelling soluble (pro)renin receptor-mediated endothelial dysfunction

Background

Preeclampsia is characterized by maternal endothelial dysfunction and new-onset hypertension. Preeclamptic pregnancies have elevated levels of maternal soluble prorenin receptor (s(P)RR) and previous studies have shown that recombinant s(P)RR produces hypertension and vascular dysfunction. This study aimed to investigate the effects of PRO20, an s(P)RR antagonist, on s(P)RR-induced endothelial dysfunction and its interaction with the Angiotensin II Type 1 Receptor (AT₁R).

Methods

Human uterine microvascular endothelial cells (HUtMECs) were treated with 100 nM s(P)RR, with/without 10 nM PRO20, 10 μM Losartan (AT₁R antagonist), or 10 μM Aliskerin (renin inhibitor). The ability of PRO20 to prevent endothelial dysfunction induced by patient serum from preeclamptic pregnancies was also assessed. Endothelial dysfunction markers were measured using immunoblot, qPCR, and ELISA. For AT₁R mechanism studies, HUtMECs were treated with control or AT₁R siRNA before s(P)RR exposure. AT₁R and s(P)RR protein structures were predicted via AlphaFold-2 and docking examined using Schrödinger.

Results

PRO20 mitigated s(P)RR-induced increases in the mRNA expression of endothelial dysfunction markers, endothelin-1, VCAM-1 and ICAM-1 and prevented s(P)RR and preeclamptic serum-induced increases in endothelin-1 and VCAM-1 protein. Aliskerin had no effect on s(P)RR-induced endothelial dysfunction. Losartan and an AT₁R siRNA were able to prevent s(P)RR induced increases in VCAM-1 protein levels and ET-1 mRNA expression, respectively. Modelling suggested that PRO20 can impair s(P)RR-AT₁R complex formation.

Conclusions

Elevated s(P)RR induces endothelial dysfunction at least partially through AT₁R. PRO20 prevents s(P)RR-AT₁R formation, suggesting it could be an effective therapeutic for preeclampsia and conditions requiring renin-angiotensin system suppression.

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来源期刊

European journal of pharmacology 医学-药学

CiteScore

9.00

自引率

0.00%

发文量

572

审稿时长

34 days

期刊介绍： The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.