Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression

Abstract

The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11β-hydroxyglucocorticoids. Variable activity of 11βHSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11βHSD2, HSD11B2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2′-deoxycytidine and procainamide enhanced the transcription and activity of the 11βHSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG-binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

“…Thus, time-course studies after UNX in the remaining kidney must be performed in order to identify relevant regulatory factors for the expression of 11b-HSD1 and 11b-HSD2. A number of factors regulating the expression of 11b-HSD enzymes have previously been identified including TNF-a, Erg1, NF-kB, NF1, C/EBPs, GR, Sp1/Sp3, Arnt, PPAR-a/PPAR-g, IL1, glucocorticoids, sex steroids, and thyroid hormones (Alikhani-Koopaei et al 2004, Tomlinson et al 2004, Kostadinova et al 2005, Alikhani-Koupaei et al 2007, Wake et al 2007, Ignatova et al 2009). The ultimate proof for a pivotal relevance of one or a combination of these factors would require the investigation of animals with specific over-or under-expression in the cortical collecting duct.…”

Epigenetic regulation of the placental HSD11B2 barrier and its role as a critical regulator of fetal development

“…46 Interestingly, hypermethylation of HSD11B2 CpG islands correlates with lower levels of HSD11B2 expression. 45 Low methylation levels of HSD11B2 were observed in the placenta (were HSD11B2 expression is high), whereas in skeletal muscle (low HSD11B2 expression) the HSD11B2 promoter was hypermethylated. 45 Furthermore, it has been shown that the activity of the HSD11B2 promoter is directly regulated by methylation.…”

“…45 Low methylation levels of HSD11B2 were observed in the placenta (were HSD11B2 expression is high), whereas in skeletal muscle (low HSD11B2 expression) the HSD11B2 promoter was hypermethylated. 45 Furthermore, it has been shown that the activity of the HSD11B2 promoter is directly regulated by methylation. 45 These data show that exposures that change HSD11B2 methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol that may adversely affect fetal development.…”

“…44,45 Hypermethylation of normally unmethylated CpG islands is indicative of transcriptional repression of the relevant gene. 46 Interestingly, hypermethylation of HSD11B2 CpG islands correlates with lower levels of HSD11B2 expression.…”

“…45 Furthermore, it has been shown that the activity of the HSD11B2 promoter is directly regulated by methylation. 45 These data show that exposures that change HSD11B2 methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol that may adversely affect fetal development. In agreement with this idea, Marsit and colleagues determined the methylation status of HSD11B2 in 186 placentae and examined any correlation with fetal birth and neurodevelopmental milestones.…”