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Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 in Glucocorticoid-Resistant Patients
Géraldine Vitellius1, Brigitte Delemer2, Philippe Caron3
1Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche_S U1185, Faculty of Medicine at Université Paris-Sud, University Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France.
Context:
Six patients carrying heterozygous loss-of-function mutations of glucocorticoid (GC) receptor (GR) presented with hypercortisolism, associated with low kalemia, low plasma renin, and aldosterone levels, with or without hypertension, suggesting a pseudohypermineralocorticism whose mechanisms remain unclear. We hypothesize that an impaired activity of the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2; encoded by the HSD11B2 gene), catalyzing cortisol (F) inactivation, may account for an inappropriate activation of a renal mineralocorticoid signaling pathway in these GC-resistant patients.
Objective:
We aim at studying the GR-mediated regulation of HSD11B2.
Design:
The HSD11B2 promoter was subcloned and luciferase reporter assays evaluated GR-dependent HSD11B2 regulation, and 11β-HSD2 expression/activity was studied in human breast cancer MCF7 cells, endogenously expressing this enzyme.
Results:
Transfection assays revealed that GR transactivated the long (2.1-kbp) HSD11B2 promoter construct, whereas a defective 501H GR mutant was unable to stimulate luciferase activity. GR-mediated transactivation of the HSD11B2 gene was inhibited by the GR antagonist RU486. A threefold increase in HSD11B2 mRNA levels was observed after dexamethasone (DXM) treatment of MCF7 cells, inhibited by RU486 or by actinomycin, supporting a GR-dependent transcription. Chromatin immunoprecipitation further demonstrated a DXM-dependent GR recruitment onto the HSD11B2 promoter. 11β-HSD2 activity, evaluated by the cortisone/F ratio, quantified by liquid chromatography/tandem mass spectrometry, was 10-fold higher in the supernatant of DXM-treated cells than controls, consistent with a GR-dependent stimulation of 11β-HSD2 catalytic activity.
Conclusion:
Collectively, we demonstrate that 11β-HSD2 expression and activity are transcriptionally regulated by GR. In the context of GR haploinsufficiency, these findings provide evidence that defective GR signaling may account for apparent mineralocorticoid excess in GC-resistant patients.
Insights
Glucocorticoid receptor (GR) signaling directly regulates 11β-HSD2 expression and activity. Impaired GR function in patients may lead to apparent mineralocorticoid excess due to defective cortisol inactivation.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Patients with glucocorticoid receptor (GR) loss-of-function mutations exhibit hypercortisolism and pseudohypermineralocorticism.
- The underlying mechanisms for this condition, particularly the role of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), remain unclear.
Purpose of the Study:
- To investigate the regulation of HSD11B2 gene expression and 11β-HSD2 enzyme activity by the GR.
- To elucidate the potential role of impaired 11β-HSD2 activity in GC-resistant pseudohypermineralocorticism.
Main Methods:
- Luciferase reporter assays using the HSD11B2 promoter to assess GR-mediated transactivation.
- Quantitative analysis of HSD11B2 mRNA levels and 11β-HSD2 enzyme activity in MCF7 cells following dexamethasone treatment.
- Chromatin immunoprecipitation to confirm GR binding to the HSD11B2 promoter.
Main Results:
- GR successfully transactivated the HSD11B2 promoter, an effect dependent on GR function and inhibited by RU486.
- Dexamethasone treatment significantly increased HSD11B2 mRNA levels and 11β-HSD2 activity in MCF7 cells, confirming GR-dependent transcriptional regulation.
- GR recruitment to the HSD11B2 promoter was confirmed via chromatin immunoprecipitation.
Conclusions:
- 11β-HSD2 expression and activity are under transcriptional control of the GR.
- Defective GR signaling in patients with GR haploinsufficiency can lead to impaired 11β-HSD2 function, contributing to apparent mineralocorticoid excess.
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