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Erythropoietin protects outer blood‐retinal barrier in experimental diabetic retinopathy by up‐regulating ZO‐1 and occludin
Author(s) -
Zhang Chaoyang,
Xie Hai,
Yang Qian,
Yang Yiting,
Li Weiye,
Tian Haibin,
Lu Lixia,
Wang Fang,
Xu JingYing,
Gao Furong,
Wang Juan,
Jin Caixia,
Xu Guoxu,
Xu GuoTong,
Zhang Jingfa
Publication year - 2019
Publication title -
clinical and experimental ophthalmology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.3
H-Index - 74
eISSN - 1442-9071
pISSN - 1442-6404
DOI - 10.1111/ceo.13619
Subject(s) - occludin , blood–retinal barrier , tight junction , medicine , retinal , diabetic retinopathy , erythropoietin , outer nuclear layer , retina , barrier function , intraperitoneal injection , streptozotocin , pharmacology , endocrinology , ophthalmology , microbiology and biotechnology , biology , diabetes mellitus , neuroscience
Purpose To explore the mechanisms of erythropoietin (EPO) in maintaining outer blood‐retinal barrier (BRB) in diabetic rats. Methods Sprague‐Dawley rats were rendered diabetic with intraperitoneal injection of streptozotocin, and then followed by intravitreal injection of EPO. Two and four weeks later, the permeability of outer BRB was examined with FITC‐dextran leakage assay, following a method to demarcate the inner and outer retina based on retinal blood supply. The glyoxal‐treated ARPE‐19 cells, incubated with EPO, soluble EPO receptor (sEPOR), Gö6976, or digoxin, were studied for cell viability and barrier function. The expressions of ZO‐1, occludin, VEGFR2, HIF‐1α, MAPKs, and AKT were examined with Western blot and immunofluorescence. Results The major Leakage of FITC‐dextran was detected in the outer nuclear layer in both 2‐ and 4‐week diabetic rats. The leakage was largely ameliorated in EPO‐treated diabetic rats. The protein expressions of ZO‐1 and occludin in the RPE‐Bruch's membrane choriocapillaris complex were significantly decreased, whereas HIF‐1α and JNK pathways were activated, in 4‐week diabetic rats. These changes were prevented by EPO treatment. The in vitro study with ARPE‐19 cells confirmed these changes, and the protective effect of EPO was abolished by sEPOR. Gö6976 and digoxin rescued the tight junction and barrier function in glyoxal‐treated ARPE‐19 cells. Conclusions In early diabetic rats, the outer BRB might be more severely damaged and its breakdown is the major factor for retinal oedema. EPO maintains the outer BRB integrity through down‐regulation of HIF‐1α and JNK signallings, and thus up‐regulating ZO‐1 and occludin expressions in RPE cells.