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<p>Prolonged use of dexamethasone (DEX) elevates intraocular pressure (IOP) and increases the risk of developing glaucoma. In a previous study, we demonstrate that DEX stimulates the expression of thrombospondin-1 (THBS1) in primary human trabecular meshwork (hTM) cells, and that inhibiting THBS1 expression prevents DEX-induced elevation of IOP in mice. Therefore, we investigate the mechanism by which DEX regulates THBS1 expression. Treatment with the DNA methylation inhibitors, 5-azacytosine (5-AC) or 5-aza-2’-deoxycytidine (5-aza-dC), upregulates THBS1 protein levels in vitro and in vivo, reduces outflow facility in perfused mouse eyes, and elevates IOP in mice. In primary hTM cells, 7-day DEX treatment results in hypomethylation of the THBS1 promoter region and reduces transcript levels of 2 DNA methyltransferases (DNMTs), DNMT1 and DNMT3A. Taken together, we show that DEX reduces expression of DNMTs and DNA methylation of the THBS1 promoter region, supporting a critical role for THBS1 in DEX-induced outflow reduction.</p>

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Hypomethylation of thrombospondin-1 promoter region is associated with reduced aqueous humor flow

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Kit Ying Choy,
  • Wei-ying Yang,
  • Choi-ying Ling,
  • King-kit Li,
  • Hoi Lam Li,
  • Hong-lok Lung,
  • Chi-ho To,
  • Chi Wai Do,
  • W. Daniel Stamer,
  • Samantha Sze-wan Shan

摘要

Prolonged use of dexamethasone (DEX) elevates intraocular pressure (IOP) and increases the risk of developing glaucoma. In a previous study, we demonstrate that DEX stimulates the expression of thrombospondin-1 (THBS1) in primary human trabecular meshwork (hTM) cells, and that inhibiting THBS1 expression prevents DEX-induced elevation of IOP in mice. Therefore, we investigate the mechanism by which DEX regulates THBS1 expression. Treatment with the DNA methylation inhibitors, 5-azacytosine (5-AC) or 5-aza-2’-deoxycytidine (5-aza-dC), upregulates THBS1 protein levels in vitro and in vivo, reduces outflow facility in perfused mouse eyes, and elevates IOP in mice. In primary hTM cells, 7-day DEX treatment results in hypomethylation of the THBS1 promoter region and reduces transcript levels of 2 DNA methyltransferases (DNMTs), DNMT1 and DNMT3A. Taken together, we show that DEX reduces expression of DNMTs and DNA methylation of the THBS1 promoter region, supporting a critical role for THBS1 in DEX-induced outflow reduction.