Kuroda, Keiji, Venkatakrishnan, R., Salker, Madhuri S., Lucas, Emma S., Shaheen, Fozia, Blanks, Andrew M., Christian, Mark, Quenby, Siobhan and Brosens, Jan J. (2013) Induction of 11beta-hydroxysteroid dehydrogenase type 1 and activation of distinct mineralocorticoid receptor- and glucocorticoid receptor-dependent gene networks in decidualizing human endometrial stromal cells. Molecular Endocrinology, 27 (2). pp. 192-202. ISSN 0888-8809.

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Abstract

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.

Item Type:	Journal Article
Subjects:	R Medicine > RA Public aspects of medicine
Divisions:	Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Reproductive Health ( - until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Endometrium, Glucocorticoids
Journal or Publication Title:	Molecular Endocrinology
Publisher:	Endocrine Society
ISSN:	0888-8809
Official Date:	February 2013
Dates:	Date Event February 2013 Published 28 December 2012 Available 8 November 2012 Accepted 27 July 2012 Submitted
Volume:	27
Number:	2
Number of Pages:	11
Page Range:	pp. 192-202
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	University Hospitals Coventry and Warwickshire NHS Trust, Warwick Medical School, Uehara Kinen Seimei Kagaku Zaidan, Naitō-Kinen-Kagaku-Shinkō-Zaidan

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