1α,25-dihydroxyvitamin D3 attenuates oxidative stress-induced damage in human trabecular meshwork cells by inhibiting TGFβ-SMAD3-VDR pathway

Abstract

Evidence indicates that 1α, 25-dihydroxy vitamin D3 (1, 25-(OH)₂D₃) markedly reduces intraocular pressure (IOP) in nonhuman primates, while the biochemical mechanisms are unclear. To investigate the influence of oxidative stress on human trabecular meshwork cells (HTMCs) and the effect and regulatory mechanism of 1, 25-(OH)₂D₃ in HTMCs under oxidative stress, we established an oxidative stress model in HTMCs using hydrogen peroxide (H₂O₂) and showed that 1, 25-(OH)₂D₃ could inhibit oxidative stress-induced apoptosis and reduce extracellular matrix (ECM) composition of HTMCs. Moreover, 1, 25-(OH)₂D₃ could attenuate H₂O₂-induced inflammation in HTMCs. Mechanistically, our findings revealed that H₂O₂-induced damage was mediated by the transforming growth factor-β (TGF-β)-SMAD3 pathway in HTMCs, and 1, 25-(OH)₂D₃ could protect HTMCs against oxidative stress through vitamin D receptor (VDR), which antagonises the effects of SMAD3. Overall, these findings define a mechanism by which 1, 25-(OH)₂D₃ reduces ECM accumulation and suppresses the TGF-β-SMAD3-VDR pathway in HTMCs, thus protecting the cells from oxidative stress, suggesting 1, 25-(OH)₂D₃ might be a potential therapeutic for glaucoma.

Keywords: 1α; 25-Dihydroxy vitamin D3; Oxidative stress; TGF-β; VDR.