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08 September 2019 : Laboratory Research  

Angiopoietin-Like Protein 4 (ANGPTL4) Induces Retinal Pigment Epithelial Barrier Breakdown by Activating Signal Transducer and Activator of Transcription 3 (STAT3): Evidence from ARPE-19 Cells Under Hypoxic Condition and Diabetic Rats

Xinyue Yang1ABCDEF, Jinfeng Cao1EF, Yang Du1BCD, Qiaoyun Gong1BCD, Yan Cheng1FG*, Guanfang Su1AG

DOI: 10.12659/MSM.915748

Med Sci Monit 2019; 25:6742-6754

Abstract

BACKGROUND: Diabetic retinopathy is a primary contributor of visual impairment in adult diabetes mellitus patients. Diabetic retinopathy causes breakdown of blood retinal barrier (BRB), and leads to diabetic macular edema. Previous studies have demonstrated angiopoietin-like protein 4 (ANGPTL4) as an effective diabetic retinopathy therapeutic target, however, its role in maintaining the outer BRB in diabetic retinopathy has yet not elucidated.

MATERIAL AND METHODS: We established an in vivo diabetic rat model with the use of streptozotocin injections and cultured ARPE-19 cells under (hypoxia, 1%) condition. We first investigated the expression of hypoxia induced factor-1α (HIF-1α) and ANGPTL4 in vivo and subsequently studied the transcriptional regulation and underlying molecular mechanisms in ARPE-19 cells under oxygen-deprived situations.

RESULTS: The expression of HIF-1α and ANGPTL4 was increased with diabetic retinopathy progression both in vivo and in vitro. Depletion of HIF-1α by siRNA inhibited hypoxia-induced ANGPTL4 expression. Repressing the HIF-1α/ANGPTL4 signaling effectively alleviated the migration and cellular permeability induced by hypoxia in ARPE-19 cells. Depletion of ANGPTL4 by siRNA significantly alleviated signal transducer and activator of transcription 3 (STAT3) activity in vitro, thereby attenuating the decrease of tight junction proteins occludin and zona occludens-1 (ZO-1) under hypoxia in ARPE-19 cells.

CONCLUSIONS: Our results suggest that ANGPTL4 partially modulates STAT3 and could serve as an effective diabetic retinopathy treatment strategy.

Keywords: Angiopoietins, Diabetic Retinopathy, STAT3 Transcription Factor, Angiopoietin-Like Protein 4, Blood Glucose, Body Weight, Cell Hypoxia, Cell Line, Cell Membrane Permeability, Diabetes Mellitus, Experimental, Disease Progression, Hypoxia-Inducible Factor 1, alpha Subunit, Models, Biological, Phenotype, RNA, Messenger, RNA, Small Interfering, retinal pigment epithelium, Streptozocin, Tight Junction Proteins, Up-Regulation

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750