ATRA protects skin fibroblasts against UV-induced oxidative damage through inhibition of E3 ligase Hrd1

All-trans retinoic acid (ATRA) can protect fibroblasts against ultraviolet (UV)-induced oxidative damage, however, its underlying molecular mechanism is still unclear. The present study aimed to investigate the role of 3-hydroxy-3-methylglutaryl reductase degradation (Hrd1) in the protective effect of ATRA on human skin fibroblasts exposed to UV. The expression of Hrd1 in human or mice skin was assessed by immunohistochemistry (IHC) staining and western blot analysis. Hrd1 siRNA (si-Hrd1) and Hrd1 recombinant adenoviruses (Ad-Hrd1) were used to downregulate and upregulate Hrd1 expression in fibroblasts, respectively. The interaction between Hrd1 and NF-E2-related factor 2 (Nrf2) was assessed by co-immunoprecipitation (co-IP) and immunofluorescence analysis. The results revealed that Hrd1 expression was increased but Nrf2 expression was decreased in UV-exposed human skin fibroblasts. In addition, ATRA could reverse the increase of Hrd1 expression induced by UV radiation in vivo and in vitro. ATRA or knockdown of Hrd1 could increase Nrf2 expression in fibroblasts exposed to UV radiation, and Hrd1 could directly interact with Nrf2 in skin fibroblasts. Notably, overexpression of Hrd1 abolished the protective effect of ATRA on the UV-induced decrease of Nrf2 expression, the production of reactive oxygen species (ROS) and the decrease of cell viability. In conclusion, the present data demonstrated that ATRA protected skin fibroblasts against UV-induced oxidative damage through inhibition of E3 ligase Hrd1.