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. 2025 Jun;182(12):2603-2620.
doi: 10.1111/bph.70007. Epub 2025 Feb 20.

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

Chiara Bianca Maria Platania  1   2 , Francesca Lazzara  1   2 , Kenneth Mitton  3 , Naomi Haque  3 , Wendelin Dailey  3 , Federica Conti  1 , Erika Giuffrida  1 , Filippo Drago  1   2 , Anca Hermenean  4 , Cornel Balta  4 , Hildegard Herman  4 , Alina Ciceu  4 , Maria Consiglia Trotta  5 , Michele D'Amico  5 , Giuseppe Nicosia  1 , Settimio Rossi  6 , Claudio Bucolo  1   2
Affiliations

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

Chiara Bianca Maria Platania et al. Br J Pharmacol. 2025 Jun.

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.

Keywords: P2X7 receptor; PLVAP; VE‐cadherin; ZO‐1; blood retinal barrier; choroid; diabetic retinopathy.

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References

REFERENCES

    1. Alexander, S. P. H., Fabbro, D., Kelly, E., Mathie, A. A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Beuve, A., Brouckaert, P., Bryant, C., Burnett, J. C., Farndale, R. W., Friebe, A., Garthwaite, J., Hobbs, A. J., Jarvis, G. E., … Waldman, S. A. (2023). The Concise Guide to PHARMACOLOGY 2023/24: Catalytic receptors. British Journal of Pharmacology, 180. Suppl, 2, S241–S288. https://doi.org/10.1111/bph.16180
    1. Alexander, S. P. H., Mathie, A. A., Peters, J. A., Veale, E. L., Striessnig, J., Kelly, E., Armstrong, J. F., Faccenda, E., Harding, S. D., Davies, J. A., Aldrich, R. W., Attali, B., Baggetta, A. M., Becirovic, E., Biel, M., Bill, R. M., Caceres, A. I., Catterall, W. A., Conner, A. C., … Zhu, M. (2023). The concise guide to pharmacology 2023/24: Ion channels. British Journal of Pharmacology, 180(Suppl 2), S145–S222. https://doi.org/10.1111/bph.16178
    1. Alexander, S. P. H., Roberts, R. E., Broughton, B. R. S., Sobey, C. G., George, C. H., Stanford, S. C., Cirino, G., Docherty, J. R., Giembycz, M. A., Hoyer, D., Insel, P. A., Izzo, A. A., Ji, Y., MacEwan, D. J., Mangum, J., Wonnacott, S., & Ahluwalia, A. (2018). Goals and practicalities of immunoblotting and immunohistochemistry: A guide for submission to the British Journal of pharmacology. British Journal of Pharmacology, 175, 407–411. https://doi.org/10.1111/bph.14112
    1. Apte, R. S., Chen, D. S., & Ferrara, N. (2019). VEGF in signaling and disease: Beyond discovery and development. Cell, 176, 1248–1264. https://doi.org/10.1016/j.cell.2019.01.021
    1. Balta, C., Herman, H., Ciceu, A., Lepre, C. C., Mladin, B., Rosu, M., Oatis, D., Russo, M., Peteu, V. E., Gherghiceanu, M., Fenyvesi, F., Cotoraci, C., Trotta, M. C., D'Amico, M., & Hermenean, A. (2024). Chrysin‐loaded calixarene‐cyclodextrin ternary drug delivery system inhibits TGF‐β and galectin‐1 mediated pathways in diabetic liver fibrosis. Biochemical Pharmacology, 229, 116474. https://doi.org/10.1016/j.bcp.2024.116474

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