Blockade of P2X7 receptors preserves blood retinal barrier integrity by modulating the plasmalemma vesicle-associated protein: Implications for diabetic retinopathy

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2025-02-20 DOI:10.1111/bph.70007

Chiara Bianca Maria Platania, Francesca Lazzara, Kenneth Mitton, Naomi Haque, Wendelin Dailey, Federica Conti, Erika Giuffrida, Filippo Drago, Anca Hermenean, Cornel Balta, Hildegard Herman, Alina Ciceu, Maria Consiglia Trotta, Michele D'Amico, Giuseppe Nicosia, Settimio Rossi, Claudio Bucolo

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引用次数: 0

Abstract

Background and Purpose

Plasmalemma vesicle-associated protein (PLVAP) regulates transcytosis in vascular endothelial cells. PLVAP expression is increased in pathological conditions, such as diabetic retinopathy. P2X7 receptor antagonists have been shown to preserve blood-retinal barrier (BRB) integrity. Here, we have tested the hypothesis that PLVAP expression is tightly linked to P2X7 receptor activity, leading to breakdown of the BRB in an in vitro model of diabetic retinopathy.

Experimental Approach

We integrated network approaches with an in vitro model of diabetic retinopathy using primary human retinal microvascular endothelial cells (HRMECs). Cells were treated with a P2X7 receptor antagonist, JNJ47965567, and expression of several genes predicted to belong to the P2X7 receptor signalling network were assessed. Levels and localisation of PLVAP, VE-cadherin and zonula occludens-1 (ZO-1) in HRMECs were evaluated. In vivo, the effects of JNJ47965567 on PLVAP expression in the retinas of diabetic mice were assessed.

Key Results

High levels of glucose increased PLVAP expression in HRMECs, which was blocked by JNJ47965567. Furthermore, JNJ47965567 preserved VE-cadherin and ZO-1. In the choroidal vasculature of diabetic mice, PLVAP immunostaining was increased, compared to levels in non-diabetic mice. This increase was significantly attenuated by treatment with JNJ47965567

Conclusions and Implications

This study showed that P2X7 receptor signalling is an important component of a complex gene regulatory network, including PLVAP, mediating the pathophysiology of diabetic retinopathy. The P2X7 receptor antagonist JNJ47965567 showed a good pharmacodynamic profile, suggesting that this approach could be of value in the treatment of diabetic retinopathy.

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P2X7受体的阻断通过调节质膜囊泡相关蛋白来保持血液视网膜屏障的完整性：对糖尿病视网膜病变的影响。

背景与目的：质膜囊泡相关蛋白（PLVAP）调节血管内皮细胞的胞吞作用。PLVAP表达在病理条件下增加，如糖尿病视网膜病变。P2X7受体拮抗剂已被证明可以保持血液-视网膜屏障（BRB）的完整性。在这里，我们在糖尿病视网膜病变的体外模型中验证了PLVAP表达与P2X7受体活性紧密相关，导致BRB分解的假设。实验方法：我们将网络方法与使用原代人视网膜微血管内皮细胞（HRMECs）的糖尿病视网膜病变体外模型相结合。用P2X7受体拮抗剂JNJ47965567处理细胞，并评估预测属于P2X7受体信号网络的几个基因的表达。评估hrmec中PLVAP、ve -钙粘蛋白和ZO-1的水平和定位。在体内，我们评估了JNJ47965567对糖尿病小鼠视网膜PLVAP表达的影响。关键结果：高水平葡萄糖增加了hrmec中PLVAP的表达，JNJ47965567阻断了这一表达。JNJ47965567保留VE-cadherin和ZO-1。在糖尿病小鼠脉络膜血管中，与非糖尿病小鼠相比，PLVAP免疫染色水平升高。结论和意义：本研究表明，P2X7受体信号是包括PLVAP在内的复杂基因调控网络的重要组成部分，介导糖尿病视网膜病变的病理生理。P2X7受体拮抗剂JNJ47965567显示出良好的药效学特征，表明该方法可能在糖尿病视网膜病变的治疗中具有价值。

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

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.