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Epigenetic Regulation of HSD11B2 Gene by Promoter Methylation in Glucocorticoid-Treated Patients

Simonetta Friso, Francesca Pizzolo, Silvia Udali, Patrizia Guarini, Annalisa Castagna, Letizia Consoli, Gianluca Salvagno, Elisa Tinazzi, Patrizia Pattini, Sang-Woon Choi, Claudio Lunardi and Oliviero Olivieri

Background: A reduced activity of the 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2) causes hypertension by conferring aldosterone selectivity to mineralcorticoid receptors and eventually impairing the tetrahydrocortisol-versus tetrahydrocortisone-metabolites (THFs/THE) shuttle. The 11 beta-HSD2 function is modulated by glucocorticoid treatment that may induce hypertension through a mechanism mostly unknown. Promoter methylation, one of the main epigenetic and potentially modifiable feature of DNA, regulates HSD11B2 gene expression and relates to the development of arterial hypertension.

Objective: To explore the mechanism by which steroid therapy influences blood pressure we investigated the effect of glucocorticoid-treatment on HSD11B2 promoter methylation and THFs/THE ratio, that reflects the 11 beta-HSD2 activity.

Method: We determined urinary THFs/THE ratio by gas chromatography/mass spectrometry and HSD11B2 methylation in promoter Region 1 and 2 using bisulfitepyrosequencing in DNA from peripheral blood mononuclear cells (PBMCs) of six normotensive subjects affected by autoimmune diseases at three time points: T0) baseline, T1) following one-month prednisone therapy (0.5-1 mg/kg daily), and T2) at least one year after withdrawal.

Results: Glucocorticoid treatment was associated with the increase of HSD11B2 promoter methylation, that was significant for Region 1 (T0 2.4%, T1 2.8%, P=0.046), and the concomitant raise of THFs/THE ratio (T0 1.29 ± 0.80, T1 4.10 ± 1.62, P=0.043). After glucocorticoid-withdrawal (T2) both parameters decreased (methylation 1.9%; THFs/THE ratio 1.09), although not significantly. A significant positive correlation was observed between HSD11B2 promoter methylation and the THFs/THE ratio.

Conclusion: High-dosage prednisone therapy alters promoter methylation of HSD11B2 and 11beta-HSD2 activity, influencing blood pressure: this effect appears slightly reversible after glucocorticoid-withdrawal, suggesting a dynamic epigenetic regulation of HSD11B2.