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20-Hydroxyecdysone activates the protective arm of the RAAS via the MAS receptor
in Journal of Molecular Endocrinology
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René Lafont
René Lafont
Biophytis, Sorbonne Université – BC9, Paris, France
Sorbonne Université, CNRS -Institut de Biologie Paris Seine (BIOSIPE), Paris, France
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Sorbonne Université, CNRS -Institut de Biologie Paris Seine (BIOSIPE), Paris, France
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Maria Serova
Maria Serova
Biophytis, Sorbonne Université – BC9, Paris, France
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Blaise Didry-Barca
Blaise Didry-Barca
Biophytis, Sorbonne Université – BC9, Paris, France
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Sophie Raynal
Sophie Raynal
Biophytis, Sorbonne Université – BC9, Paris, France
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Louis Guibout
Louis Guibout
Biophytis, Sorbonne Université – BC9, Paris, France
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Laurence Dinan
Laurence Dinan
Biophytis, Sorbonne Université – BC9, Paris, France
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Stanislas Veillet
Stanislas Veillet
Biophytis, Sorbonne Université – BC9, Paris, France
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Mathilde Latil
Mathilde Latil
Biophytis, Sorbonne Université – BC9, Paris, France
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Waly Dioh
Waly Dioh
Biophytis, Sorbonne Université – BC9, Paris, France
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Pierre J Dilda
https://orcid.org/0000-0001-9916-8513
Pierre J Dilda
Biophytis, Sorbonne Université – BC9, Paris, France
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20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysteroid receptors (EcR/RXR complex) and at least one membrane GPCR receptor (DopEcR). It also displays numerous pharmacological effects in mammals, where its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ERβ receptor. The goal of this study was to better understand 20E mechanism of action in mammals. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) were 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 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 the 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, the proposed mechanism may explain the close similarity between the effects of angiotensin(1–7) and 20E. Our findings open up many possible therapeutic developments involving stimulation of the protective arm of the renin–angiotensin–aldosterone system (RAAS) with 20E.
Supplementary Materials
- Supplementary Materials
- Supporting Table 1: Effect of 20-hydroxyecdysone on 45 selected GPCR and 5 nuclear receptors. Effect of 20-hydroxyecdysone on 45 selected GPCR and 5 nuclear receptors. 20-Hydroxyecdysone was employed at a fixed concentration of 10 μM in radioligand binding assays involving specific ligands of a selection of GPCR and nuclear receptors. The percentage of specific ligand binding inhibition produced by 20E at 10 μM in duplicate experiments is presented. None of these inhibitions were considered significant (< 30 % inhibition at 10 μM).
- Supporting Table 2. The close similarity of Angiotensin (1-7), AVE 0991, 20E and estradiol effects.
- Supporting Figure S1: Proposed mechanism of 20E membrane action (redrawn and modified from Gorelick-Feldman et al., 2010) Gq: a subtype of G protein; PLC: Phospholipase C; PIP2: Phosphatidylinositol 4,5- bisphosphate; IP3:Inositol triphosphate; IP3R: Inositol triphosphate receptor; PI3K: phosphoinositide 3-kinase, PDK: Pyruvate dehydrogenase kinase; AKT: Protein kinase B; EGTA: ethylene glycol tetraacetic acid, a calcium chelator; PTX: an inhibitor of G-protein coupled receptors; U-73122: an inhibitor of agonist-induced PLC activation; LY-294002: a potent inhibitor of phosphoinositide 3-kinases; BAPTA-AM: 1,2-bis(o-phenoxy)ethane- N,N,N',N'-tetraacetic acid, a membrane permeable calcium chelator; 2APB: 2- Aminoethoxydiphenylborate, an inhibitor of IP3R and Transient Receptor Potential channel.
- Supporting Figure S2: 20-Hydroxyecdysone induction of NO production is mediated through Mas receptor activation. (A) MAS mRNA expression was evaluated by qRTPCR in HEK293 human embrionic kidney, AB116720FLCL1 (AB1167) human fascia lata muscle and MCF7 human breast cancer cell lines (A). MCF7 cells were treated for 30 minutes with 1, 5 or 10 µM 20E or angiotensin-(1-7) with or without Mas antagonist (A779, 10 µM). (B) NO production was determined using DAF-FM fluorescence. Results are shown as means ± SEM of at least 6 independent experiments with *p < 0.05; **p < 0.01; ***p < 0.001. Kruskal-Wallis one-way ANOVA followed by uncorrected Dunn’s test compared to controls.
- Supporting Figure S3: Inhibitory activity of 17α-estradiol (αE2) on myostatin gene expression. Differentiated C2C12 cells were treated with IGF-1 (100 ng/mL) or α-estradiol (0.01, 0.1 and 1 µM) for 6 h. Myostatin gene expression was analysed by qRT-PCR. Results are shown as means ± SEM of 7 independent experiments. Kruskal-Wallis one-way ANOVA followed by uncorrected Dunn’s test was performed with **p < 0.01 compared to untreated control.
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Online ISSN: 1479-6813
Print ISSN: 0952-5041
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