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 W. Stitt, Koh Hei Sonoda

研究成果: ジャーナルへの寄稿学術誌査読

41 被引用数 (Scopus)


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 (CD11b1 Ly6C1 CCR21 cells), macrophage/microglia activation (CD11b1 CD801 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 rho-associated coiled-coil–containing protein kinase (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.

出版ステータス出版済み - 5月 1 2020

!!!All Science Journal Classification (ASJC) codes

  • 内科学
  • 内分泌学、糖尿病および代謝内科学


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