Induction of 11β-HSD 1 and Activation of Distinct Mineralocorticoid Receptor- and Glucocorticoid Receptor-Dependent Gene Networks in Decidualizing Human Endometrial Stromal Cells
Open accessAbstract
The actions of glucocorticoids at the feto-maternal interface are not well understood. Here, we show that decidualization of human endometrial stromal cells (HESCs) in response to progesterone and cAMP signaling is associated with a strong induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) expression and enzyme activity. Decidualization also triggered a gradual decrease in glucocorticoid receptor (GR) expression and reciprocal increase in mineralocorticoid receptor (MR) levels. Gene expression profiling of differentiating HESCs after small interfering RNA (siRNA)-mediated knockdown of either GR or MR identified 239 and 167 significantly regulated genes, respectively. Interestingly, GR-repressed genes were enriched for Krüppel-associated box domain containing zinc-finger proteins, transcriptional repressors involved in heterochromatin formation. In agreement, GR knockdown was sufficient to enhance trimethylated H3K9 levels in decidualizing cells. Conversely, we identified several MR-dependent genes implicated in lipid droplet biogenesis and retinoid metabolism. For example, the induction in differentiating HESCs of DHRS3, encoding a highly conserved enzyme that catalyzes the oxidation/reduction of retinoids and steroids, was enhanced by aldosterone, attenuated in response to MR knockdown, and abolished upon treatment with the MR antagonist RU26752. Furthermore, we demonstrate that decidualization is associated with dynamic changes in the abundance and distribution of cytoplasmic lipid droplets, the formation of which was blocked by RU26752. In summary, progesterone drives local cortisol biosynthesis by decidual cells through induction of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), leading to transcriptional regulation of distinct GR and MR gene networks involved in epigenetic programming and lipid and retinoid metabolism, respectively.
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Human endometrial stromal cells decidualized ex vivo demonstrate distinct GR and MR transcriptional networks.
“Human endometrial stromal cells decidualized ex vivo demonstrate distinct GR and MR transcriptional networks, suggesting stress signaling through release of cortisol and aldosterone may impact uterine physiology through independent mechanisms [58].”
From Stress and the HPA Axis: Balancing Homeostasis and Fertility. (2017) · cites this paper as [58]
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Stress and the HPA Axis: Balancing Homeostasis and Fertility.
Joseph, D., & Whirledge, S. (2017) · International journal of molecular sciences · doi:10.3390/ijms18102224 · Cited by 290 · see citing works
“Human endometrial stromal cells decidualized ex vivo demonstrate distinct GR and MR transcriptional networks, suggesting stress signaling through release of cortisol and aldosterone may impact uterine physiology through independent mechanisms [58].”
BackgroundGlucocorticoids and reproduction: Traffic control on the road to reproduction
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- Authors
- Kuroda, K., Venkatakrishnan, R., Salker, M. S., Lucas, E. S., Shaheen, F., Kuroda, M., Blanks, A., Christian, M., Quenby, S., & Brosens, J. J.
- Affiliations
- University Hospital Coventry (GB)
- University of Warwick (GB)
- Hammersmith Hospital (GB)
- Juntendo University (JP)
- Corresponding author
- Brosens, Jan J.
- ORCID
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2013-02-01
- Volume
- 27
- Issue
- 2
- Pages
- 192-202
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- PMC
- PMC5417328
- OpenAlex
- W2060485475
- Cited by
- 63
- References
- 9
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 6 · 2022: 1 · 2021: 6 · 2020: 11 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 6 · 2015: 1 · 2014: 4 · 2013: 5
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Warwick
- University Hospitals Coventry and Warwickshire NHS Trust
- Warwick Medical School
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- 11β-hydroxysteroid dehydrogenase type 1, decidualization, endometrial stromal cells, mineralocorticoid receptor, glucocorticoid receptor, progesterone, cAMP signaling, cortisol production, maternal-fetal interface, H3K9 trimethylation, heterochromatin, lipid droplet formation, vitamin A metabolism, DHRS3, aldosterone, gene expression profiling
- MeSH terms
- Cyclic AMP, Mineralocorticoid Receptor Antagonists, Cell Differentiation, Cells, Cultured, Decidua, Endometrium, Female, Gene Expression Regulation, Humans, Hydrocortisone, Lipids, Progesterone, Receptors, Glucocorticoid, Retinoids, Roxithromycin, Zinc Fingers, Stromal Cells, Receptors, Mineralocorticoid, Gene Expression Profiling, RNA Interference, RNA, Small Interfering, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Kruppel-Like Transcription Factors, Gene Regulatory Networks
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