Polydatin attenuates orbital oxidative stress in Graves' orbitopathy through the NRF2 pathway

Graves' orbitopathy (GO) is a sight-threatening ocular disease that occurs in patients with hyperthyroidism and is especially associated with oxidative stress. Polydatin (PD) is a major active component of Polygonum cuspidatum Sieb. et Zucc. It has various therapeutic effects including anti-inflammatory and antioxidant properties. In the present study, we investigated the effects of PD on H₂O₂-induced oxidative stress in orbital fibroblasts in vitro and in a GO mouse model of orbital oxidative stress in vivo. The mechanisms responsible for these effects were investigated using standard molecular techniques. Our initial findings in GO mice were that PD attenuated orbital muscle adipose tissue expansion and lipid droplet accumulation through a nuclear factor E2-related factor 2 (NRF2)-mediated oxidative stress response involving the Keap1/Nrf2/ARE pathway. The results demonstrated that PD could reverse the accumulation of lipid droplets and production of reactive oxygen species (ROS) induced by H₂O₂ and increase the expression of antioxidant genes such as NAD(P)H dehydrogenase, quinone 1 (NQO1). NQO1 levels were the lowest in the GO mouse model. In addition, PD enhanced NRF2 nuclear translocation in cultured orbital fibroblasts. We also found that silencing NRF2, using RNA interference, reduced the protective effects of PD against H₂O₂-induced oxidative stress in orbital fibroblasts in vitro. Taken together, our results indicate that PD can reduce the production of ROS and inhibit adipogenesis in orbital fibroblasts in vitro and in vivo.