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.

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

• Authors: Xinyue Yang, Jinfeng Cao, Yang Du, Qiaoyun Gong, Yan Cheng, Guanfang Su
• Journal: Medical science monitor : international medical journal of experimental and clinical research (Med Sci Monit) Vol. 25 Pg. 6742-6754 (Sep 08 2019) ISSN: 1643-3750 [Electronic] United States
• PMID: 31494661 (Publication Type: Journal Article)

Chemical References

• Angiopoietin-Like Protein 4
• Blood Glucose
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• RNA, Small Interfering
• STAT3 Transcription Factor
• Tight Junction Proteins
• Streptozocin

Topics

• Angiopoietin-Like Protein 4 (genetics, metabolism)
• Animals
• Blood Glucose (metabolism)
• Body Weight
• Cell Hypoxia
• Cell Line
• Cell Membrane Permeability
• Cell Movement
• Diabetes Mellitus, Experimental (blood, genetics, metabolism, pathology)
• Disease Progression
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Models, Biological
• Phenotype
• RNA, Messenger (genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Rats, Sprague-Dawley
• Retinal Pigment Epithelium (metabolism, pathology)
• STAT3 Transcription Factor (genetics, metabolism)
• Streptozocin
• Tight Junction Proteins (metabolism)
• Up-Regulation (genetics)