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Updated: Jun 22, 2026
Characterization of a Novel Human Organotypic Retinal Culture Technique
Published on: June 9, 2021
Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary
Lorena Perrone1, Takhellambam S Devi, Ken-ichi Hosoya
1Department of Anatomy/Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Abstract:
Chronic hyperglycemia and activation of receptor for advanced glycation end products (RAGE) are known risk factors for microvascular disease development in diabetic retinopathy. Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of antioxidant thioredoxin (TRX), plays a causative role in diabetes and its vascular complications. Herein we investigate whether HG and RAGE induce inflammation in rat retinal endothelial cells (EC) under diabetic conditions in culture through TXNIP activation and whether epigenetic mechanisms play a role in inflammatory gene expression. We show that RAGE activation by its ligand S100B or HG treatment of retinal EC induces the expression of TXNIP and inflammatory genes such as Cox2, VEGF-A, and ICAM1. TXNIP silencing by siRNA impedes RAGE and HG effects while stable over-expression of a cDNA for human TXNIP in EC elevates inflammation. p38 MAPK-NF-kappaB signaling pathway and histone H3 lysine (K) nine modifications are involved in TXNIP-induced inflammation. Chromatin immunoprecipitation (ChIP) assays reveal that TXNIP over-expression in EC abolishes H3K9 tri-methylation, a marker for gene inactivation, and increases H3K9 acetylation, an indicator of gene induction, at proximal Cox2 promoter bearing the NF-kappaB-binding site. These findings have important implications toward understanding the molecular mechanisms of ocular inflammation and endothelial dysfunction in diabetic retinopathy.
Insights
High glucose and RAGE activation trigger inflammation in diabetic retinopathy by upregulating TXNIP, a key protein. Epigenetic changes in histone modifications influence inflammatory gene expression, offering insights into diabetic eye disease.
Area of Science:
- Ophthalmology
- Endocrinology
- Molecular Biology
Background:
- Diabetic retinopathy involves microvascular complications driven by chronic hyperglycemia and RAGE activation.
- TXNIP, an inhibitor of antioxidant thioredoxin, is implicated in diabetes and vascular issues.
Purpose of the Study:
- To investigate if high glucose (HG) and RAGE induce inflammation in rat retinal endothelial cells (EC) via TXNIP activation.
- To explore the role of epigenetic mechanisms in HG- and RAGE-induced inflammatory gene expression.
Main Methods:
- Retinal EC were treated with HG or RAGE ligand (S100B).
- TXNIP expression was manipulated using siRNA and cDNA over-expression.
- Signaling pathways (p38 MAPK-NF-kappaB) and histone modifications (H3K9 methylation/acetylation) were analyzed.
- Chromatin immunoprecipitation (ChIP) assays were performed on the Cox2 promoter.
Main Results:
- HG and RAGE activation increased TXNIP, Cox2, VEGF-A, and ICAM1 expression in retinal EC.
- TXNIP silencing reduced HG and RAGE effects; TXNIP over-expression enhanced inflammation.
- The p38 MAPK-NF-kappaB pathway and H3K9 modifications were involved in TXNIP-induced inflammation.
- TXNIP over-expression altered H3K9 methylation and acetylation at the Cox2 promoter.
Conclusions:
- TXNIP activation is a critical mediator of inflammation in diabetic retinopathy induced by HG and RAGE.
- Epigenetic modifications, specifically H3K9 acetylation/methylation, play a significant role in regulating inflammatory gene expression.
- These findings elucidate molecular mechanisms underlying ocular inflammation and endothelial dysfunction in diabetes.
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