Protective Effects of 1,25 Dihydroxyvitamin D3 against High-Glucose-Induced Damage in Human Umbilical Vein Endothelial Cells Involve Activation of Nrf2 Antioxidant Signaling

Abstract

Aim: To explore the protective effects and related mech­anisms of 1,25 dihydroxyvitamin D₃ (1,25(OH)₂D₃) on en­dothelial dysfunction under hyperglycemic conditions. Methods: Cultured human umbilical vein endothelial cells (HUVECs) were treated with normal glucose (glucose concentration of 5.5 mmol/L), high glucose (glucose concentration of 33 mmol/L), and high glucose plus 1,25(OH)₂D₃, respectively. Cell viability and apoptosis, intracellular reactive oxygen species (ROS) and nitric oxide (NO) contents, antioxidant enzyme activities, proinflammatory cytokine mRNA levels, and expression levels of proteins involved were measured. Results: High glucose decreased HUVEC viability, promoted ROS production and apoptosis, and reduced NO generation, which was associated with decreased activities of antioxidant enzymes and increased levels of proinflam­matory cytokines. 1,25(OH)₂D₃ treatment enhanced HUVEC viability, attenuated ROS generation and apoptosis, and ­increased NO production, which was accompanied by ­enhanced antioxidant enzyme activities and reduced ­proinflammatory factors. Mechanically, 1,25(OH)₂D₃ promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in a vitamin D receptor (VDR)-dependent manner, and Nrf2 siRNA abolished the antioxidative and ­anti-inflammatory effects of 1,25(OH)₂D₃. Conclusions: 1,25(OH)₂D₃ attenuates high-glucose-induced endothelial oxidative injury through upregulation of the Nrf2 antioxidant pathway in a VDR-dependent manner.