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The Vitamin D Receptor As A Therapeutic Target In Oxidative Stress And Nrf‐2 Signaling: Role Of Vitamin D And Urolithin A
Author(s) -
Sabir Zhela,
Livingston Sarah,
Whitfield Kerr,
Haussler Mark,
Jurutka Peter
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01852
Subject(s) - calcitriol receptor , vitamin d and neurology , retinoid x receptor , chemistry , oxidative stress , hek 293 cells , retinoic acid , microbiology and biotechnology , receptor , biology , biochemistry , nuclear receptor , endocrinology , transcription factor , gene
Vitamin D is an essential nutrient, commonly acquired via dietary intake and/or from endogenous cutaneous synthesis in response to ultraviolet radiation. The biologically active form of vitamin D, 1,25‐dihydroxyvitamin D (1,25D), binds to the vitamin D receptor (VDR) and stimulates formation of an active hetero‐complex with the retinoid X receptor (RXR). This VDR‐RXR heterodimer controls vitamin D‐regulated genes in such target tissues as kidney and colon, modulates immune defenses, and controls cellular proliferation. VDR may also play a significant role in preventing oxidative damage, potentially delaying the aging process, and serving as an anti‐carcinogenic mediator. We hypothesize that VDR may target genes encoding antioxidant enzymes which contain antioxidant‐responsive elements (AREs) that act as binding sites for transcriptional regulators such as nuclear factor (erythroid‐derived 2)‐like 2 (Nrf‐2). This study aims to investigate the influence of vitamin D‐VDR signaling on Nrf‐2 activity. In order to probe a possible molecular mechanism, an ARE‐luciferase reporter plasmid was employed to measure Nrf‐2 activity in human embryonic kidney cells (HEK‐293) in the presence of 1,25D/VDR. Results indicate cells transfected with both Nrf‐2 and VDR displayed Nrf‐2 activity that was modulated in a 1,25D‐ and VDR‐dependent manner; with low 1,25D enhancing Nrf‐2 activity while higher concentrations inhibited Nrf‐2. When treating cells with 1,25D and/or urolithin‐A (UA), a nutraceutical hypothesized to cooperate with vitamin D, Nrf‐2 activity was instead consistently upregulated. Moreover, in qPCR studies with Nrf‐2 target genes GCLC and HMOX1, UA and 1,25D treatment resulted in similar enhancement and/or suppression of Nrf‐2, consistent with the luciferase‐based assays. Collectively, these results imply that VDR likely targets Nrf‐2 genes indirectly perhaps by influencing the activity of Nrf‐2 transfactors and/or by post‐translational modification of Nrf‐2 to either activate or suppress Nrf‐2‐directed gene regulation. The modulation of Nrf‐2 activity by a VDR‐mediated pathway identifies a possible regulatory role for vitamin D in anti‐oxidation and establishes the significance of vitamin D to human senescence and aging.