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

Abstract

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.

Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich’s Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress

“…The primer sequences used in this study were synthesized by Genewiz (South Plainfield, NJ, USA), as shown in Table 1 . Amplification was performed for 40 cycles in the StepOne Plus™ Real-Time PCR System (Applied Biosystems Inc., Foster City, CA, USA) [ 39 , 40 , 41 ]. The expression of the gene of interest was normalized to the reference gene actin beta ( ACTB ).…”

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis — a systematic review

“…As regards the impact of VA on Nrf2 signaling, current literature remains inconclusive. Several studies reported that administration of VA led to restoration of Nrf2, along with mitigation of OS; however, the authors did not evaluate whether the antioxidative effect of VA was exerted exclusively through Nrf2 signaling (Wang et al 2014;Cheng et al 2019;Wu 2022;Latief et al 2019). On the contrary, Yin et al (Yin et al 2015) reported that ATRA reduced the expression of Nrf2 and HO-1 in glial cells, resulting in enhanced inflammation and OS of brain tissue after intracerebral hemorrhage.…”

Retinoic Acid and Its Derivatives in Skin

“…It is well documented that ATRA is able to protect fibroblasts and other skin cells against UV radiation-induced oxidative damage. A study conducted by Cheng et al, 2019 [ 48 ], concluded that ATRA significantly induces Nrf2 (nuclear factor erythroid 2–related factor 2). E3 ligase Hrd1 induces Nrf2 ubiquitylation and degradation in embryonic fibroblast cells in response to oxidative stress, while Nrf2 acts as an ATRA-activated photoprotective agent in the skin regeneration.…”