Claudin-5 Redistribution Induced by Inflammation Leads to Anti-VEGF Resistant Diabetic Macular Edema

Mitsuru Arima, Shintaro Nakao, Muneo Yamaguchi, Hao Feng, Yuya Fujii, Kensuke Shibata, Iori Wada, Yoshihiro Kaizu, Hamid Ahmadieh, Tatsuro Ishibashi, Alan Stitt, Koh-Hei Sonoda

Research output: Contribution to journalArticle

Abstract

Approximately 40% of patients with diabetic macular edema (DME) are resistant to anti-vascular endothelial growth factor (VEGF) therapy (rDME). Here, we demonstrate that significant correlations between inflammatory cytokines and VEGF, as observed in naive DME, are lost in patients with rDME. VEGF overexpression in the mouse retina caused delayed inflammatory cytokine upregulation, monocyte/macrophage infiltration (CD11b+ Ly6C+ CCR2+ cells), macrophage/microglia activation (CD11b+ CD80+ cells), and blood-retinal barrier disruption due to claudin-5 redistribution, which did not recover with VEGF blockade alone. Phosphorylated protein analysis of VEGF-overexpressed retinas revealed ROCK activation. Administration of ripasudil, a selective ROCK inhibitor, attenuated retinal inflammation and claudin-5 redistribution. Ripasudil also contributed to the stability of claudin-5 expression by both transcriptional enhancement and degradation suppression in inflammatory cytokine-stimulated endothelium. Notably, the anti-VEGF agent and the ROCK inhibitor were synergic in suppressing cytokine upregulation, monocyte/macrophage infiltration, macrophage/microglia activation, and claudin-5 redistribution. Furthermore, in vitro analysis confirmed that claudin-5 redistribution depends on ROCK2, but not on ROCK1. This synergistic effect was also confirmed in human rDME cases. Our results suggest that ROCK-mediated claudin-5 redistribution by inflammation is a key mechanism in the anti-VEGF resistance of DME.

Original languageEnglish
JournalDiabetes
Volume69
Issue number3
Early online date05 Mar 2020
DOIs
Publication statusEarly online date - 05 Mar 2020
Externally publishedYes

Bibliographical note

© 2020 by the American Diabetes Association.

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    Arima, M., Nakao, S., Yamaguchi, M., Feng, H., Fujii, Y., Shibata, K., Wada, I., Kaizu, Y., Ahmadieh, H., Ishibashi, T., Stitt, A., & Sonoda, K-H. (2020). Claudin-5 Redistribution Induced by Inflammation Leads to Anti-VEGF Resistant Diabetic Macular Edema. Diabetes, 69(3). https://doi.org/10.2337/db19-1121