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

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/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-1 alpha (HIF-1 alpha) 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-1 alpha and ANGPTL4 was increased with diabetic retinopathy progression both in vivo and in vitro. Depletion of HIF-1 alpha by siRNA inhibited hypoxia-induced ANGPTL4 expression. Repressing the HIF-1 alpha/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.