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Ryoichi Arita, Shintaro Nakao, Muneo Yamaguchi, Tomoyuki Isobe, Yoshio Kaneko, Tatsuro Ishibashi; Therapeutic potential of topical ROCK inhibitor K-115 in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1261.
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© ARVO (1962-2015); The Authors (2016-present)
Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and vascular leakage in diabetic retinopathy. Anti-VEGF therapy is widely used for these pathological conditions. However, frequent intravitreal injections are needed for maximum effect. In this study, we investigated the therapeutic potential of the topical ROCK (Rho-associated protein kinase) inhibitor K-115 in pathological retinal neovascularization and vascular leakage.
In vitro, human retinal microvascular endothelial cells (HRVECs) were pretreated with K-115 (3µM, 30µM), and then stimulated with human recombinant VEGF (25ng/ml). Migration and proliferation ability were assessed by cell migration and proliferation assay, respectively. The expression and localization of tight junction proteins (occludin/claudin) were evaluated by western blotting and immunohistochemistry, respectively. In vivo, normal saline vehicle, 0.4% or 0.8% K-115 eye drops were administered topically three times a day from postnatal day (P) 12 to P17 to both eyes of mice with oxygen-induced retinopathy (OIR). The areas of neovascularization/avascular retina and fluorescein leakage were quantified with retinal flat-mounts and fluorescein angiography at P17, respectively.
K-115 significantly inhibited VEGF-induced HRVECs migration (26.2% reduction at 3µM, 43.2% reduction at 30µM, P<0.01 respectively) and proliferation (39.5% reduction at 3µM, 45.1% reduction at 30µM, P<0.05 respectively) in a dose-dependent manner. Tight junction proteins (occluding, claudin) were disassembled from intercellular junctions in VEGF simulated HRVECs, and this was tended to prevented with K-115 pretreatment. In the K-115 eye drop-treated mice, the areas of neovascularization in the flat-mount retina showed a significant reduction compared to those of the vehicle-treated mice (41.8% reduction at 0.4% K-115, 47.3% reduction at 0.8% K-115, P<0.01 respectively). Moreover, K-115 eye drops significantly reduced the areas of avascular retina in a dose-dependent manner (23% reduction at 0.4% K-115, 41.9% reduction at 0.8% K-115, P<0.01 respectively). The areas of fluorescein leakage were also significantly reduced in 0.8% K-115-treated mice compared with vehicle-treated mice (58.4% reduction, P<0.05).
Topical K-115 treatment has the potential to become a novel therapeutic strategy in the treatment of diabetic retinopathy.
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