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20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor

René Lafont, Sophie Raynal, Maria Serova, Blaise Didry-Barca, View ORCID ProfileLouis Guibout, Mathilde Latil, Pierre J. Dilda, Waly Dioh, Stanislas Veillet
doi: https://doi.org/10.1101/2020.04.08.032607
René Lafont
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
2Sorbonne Université, CNRS - Institut de Biologie Paris Seine (BIOSIPE), 75005 Paris, France
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Sophie Raynal
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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Maria Serova
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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Blaise Didry-Barca
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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Louis Guibout
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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  • ORCID record for Louis Guibout
Mathilde Latil
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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Pierre J. Dilda
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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  • For correspondence: pierre.dilda@biophytis.com
Waly Dioh
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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Stanislas Veillet
1Biophytis, Sorbonne Université – BC9, 4 place Jussieu, 75005 Paris, France
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ABSTRACT

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysone receptors (EcRs) and at least one membrane GPCR receptor (DopEcR) and displays numerous pharmacological effects in mammals. However, its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERβ receptor. The goal of our study was to better understand 20E mechanism of action.

A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) was used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with Angiotensin-(1-7), the endogenous ligand of Mas. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using small interfering RNA (siRNA) or pharmacological inhibitors.

17β-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin-(1-7) antagonists. A mechanism involving cooperation between Mas receptor and a membrane-bound palmitoylated estrogen receptor is proposed.

The possibility to activate the Mas receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and indeed this mechanism may explain the close similarity between angiotensin-(1-7) and 20E effects. Our findings open a lot of possible therapeutic developments by stimulating the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.

  • Abbreviations

    (20E)
    20-Hydroxyecdysone,
    (17α-E2)
    17α-Estradiol,
    (E2)
    17β-Estradiol,
    (HCCA)
    α-cyano-4-hydrocinnamic acid,
    (AR)
    androgen receptor,
    (Ang1-7)
    angiotensin-(1-7),
    (AT1R)
    angiotensin II receptor type 1,
    (A779)
    Asp-Arg-Val-Tyr-Ile-His-D-Ala,
    (A1)
    Asp-Arg-Val-Tyr-Ile-His-D-Pro,
    (BSA)
    bovine serum albumin,
    (CMO)
    carboxymethyloxime,
    (cAMP)
    cyclic adenosine monophosphate,
    (cGMP)
    cyclic guanosine monophosphate,
    (DAG)
    diacylglycerol,
    (DMSO)
    dimethyl sulfoxide,
    (DopEcR)
    dopamine/ecdysteroid receptor,
    (DMEM)
    Dulbecco’s Modified Eagle Medium,
    (EcR)
    ecdysone receptor,
    (ERβ)
    estrogen receptor β,
    (ERα)
    estrogen receptor α,
    (ERs)
    estrogen receptors,
    (GR)
    glucocorticoid receptor,
    (GPCR)
    G protein-coupled receptor,
    (GPR30)
    G protein-coupled receptor 30,
    (GPER)
    G protein-coupled estrogen receptor 1,
    (TGR5)
    G-protein-coupled bile acid receptor,
    (Gq)
    G-protein subtype q,
    (HSA)
    human serum albumin,
    (HUVEC)
    human umbilical vein endothelial cells,
    (HPRT)
    hypoxanthine guanine phosphoribosyl transferase,
    (IP3)
    inositol trisphosphate,
    (IGF-1)
    insulin growth factor,
    (IGFR)
    insulin growth factor receptor,
    (MALDI TOF/TOF)
    matrix-assisted laser desorption ionization - tandem time-of-flight,
    (LD50)
    membrane-associated, lethal dose 50%,
    (NO)
    nitric oxide,
    (NOS)
    nitrous oxide synthase,
    (QRT-PCR)
    quantitative reverse transcriptase polymerase chain reaction,
    (MARRS)
    rapid response steroid-binding receptor,
    (7TD)
    seven transmembrane domains,
    (siRNA)
    small interfering RNA,
    ([3H]-Leu)
    tritiated leucine,
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    Posted April 10, 2020.
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    20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor
    René Lafont, Sophie Raynal, Maria Serova, Blaise Didry-Barca, Louis Guibout, Mathilde Latil, Pierre J. Dilda, Waly Dioh, Stanislas Veillet
    bioRxiv 2020.04.08.032607; doi: https://doi.org/10.1101/2020.04.08.032607
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    20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor
    René Lafont, Sophie Raynal, Maria Serova, Blaise Didry-Barca, Louis Guibout, Mathilde Latil, Pierre J. Dilda, Waly Dioh, Stanislas Veillet
    bioRxiv 2020.04.08.032607; doi: https://doi.org/10.1101/2020.04.08.032607

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