Experimental eye research · 2026
To delineate the role of Zinc Alpha 2 Glycoprotein in the pathophysiology of diabetic retinopathy using in vitro models of retinal endothelial cells and pericytes.
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Babu Ramya Benita, Shajahan Sathik, Arumugam Kishore, Rajesh Bharathidevi Subramaniam
Аннотация
PURPOSE: To study the mechanistic role of Zinc Alpha 2 Glycoprotein (ZAG) in the pathophysiology of Diabetic Retinopathy (DR) through in vitro models.
METHODS: Human retinal endothelial cells (HREC) and Human Retinal Pericytes (HRP) were cultured under normal glucose (5.5 mM) and high glucose (25 mM) conditions and then exposed to recombinant ZAG. Gene expression of metabolic markers was analysed by qPCR and validated through the gene silencing experiment. To evaluate the functional importance of ZAG in vitro, the tube formation and wound-healing assay were performed.
RESULT: ZAG was previously recognised as a clinical risk factor for DR. High glucose induced ZAG mRNA expression in HREC but not in HRP. High-glucose stimulation significantly elevated the expression of ZAG-regulated genes. The supplementation of recombinant ZAG increased metabolic markers, such as PPAR-γ and UCP, while simultaneously decreasing the TNF-α, an inflammatory marker and VEGF, an angiogenic marker, in HREC. Gene silencing reversed these changes. ZAG promoted lipolysis and reduced lipid droplet accumulation in Pericytes. Functional assays demonstrated that ZAG reduced angiogenesis by inhibiting tube formation and reducing wound closure, particularly under high-glucose conditions.
CONCLUSION: ZAG has functional relevance in influencing inflammatory, metabolic, and angiogenic pathways in retinal endothelial cells and pericytes. Evidence from functional assays support its protective effect and potential therapeutic relevance in diabetic retinopathy. This is the first study to demonstrate ZAG's multimodal protective activity in both retinal cell types, highlighting it as a promising target for future translational research.
METHODS: Human retinal endothelial cells (HREC) and Human Retinal Pericytes (HRP) were cultured under normal glucose (5.5 mM) and high glucose (25 mM) conditions and then exposed to recombinant ZAG. Gene expression of metabolic markers was analysed by qPCR and validated through the gene silencing experiment. To evaluate the functional importance of ZAG in vitro, the tube formation and wound-healing assay were performed.
RESULT: ZAG was previously recognised as a clinical risk factor for DR. High glucose induced ZAG mRNA expression in HREC but not in HRP. High-glucose stimulation significantly elevated the expression of ZAG-regulated genes. The supplementation of recombinant ZAG increased metabolic markers, such as PPAR-γ and UCP, while simultaneously decreasing the TNF-α, an inflammatory marker and VEGF, an angiogenic marker, in HREC. Gene silencing reversed these changes. ZAG promoted lipolysis and reduced lipid droplet accumulation in Pericytes. Functional assays demonstrated that ZAG reduced angiogenesis by inhibiting tube formation and reducing wound closure, particularly under high-glucose conditions.
CONCLUSION: ZAG has functional relevance in influencing inflammatory, metabolic, and angiogenic pathways in retinal endothelial cells and pericytes. Evidence from functional assays support its protective effect and potential therapeutic relevance in diabetic retinopathy. This is the first study to demonstrate ZAG's multimodal protective activity in both retinal cell types, highlighting it as a promising target for future translational research.