title: Histone deacetylase inhibition, but not a mineralocorticoid receptor antagonist spironolactone, attenuates atypical transcription by an activating mutant MR (MRS 810L ).
abstract: A mutation in the mineralocorticoid receptor (MRS 810L ) leads to early-onset hypertension, which is markedly exacerbated during pregnancy. The mutation causes progesterone and even the MR antagonist spironolactone to become potent agonists. Thus, it is hard to control hypertension in patients harbouring this mutation. We hypothesized that histone deacetylase inhibition (HDACi), but not the MR antagonist spironolactone, attenuates atypical transcriptional activity of activating mutant MR (MRS 810L ). We established HEK293T cells overexpressing wild-type MR (MRWT ) or MRS 810L and determined their transcriptional activities by luciferase assay. Expression of MR target genes was measured by quantitative real-time PCR (qRT-PCR). Treatment with aldosterone increased the expression of MR target genes as well as the transcriptional activities in HEK293T cells transfected either with MRWT or MRS 810L . Treatment with either spironolactone or progesterone also increased the expression of MR target genes as well as transcriptional activity, but only in HEK293T cells transfected with MRS 810L . Spironolactone abolished the promoter activity stimulated by aldosterone in HEK293T cells transfected with MRWT . Treatment with HDAC inhibitors attenuated the transcriptional activity as well as the expression of MR target genes induced by aldosterone, spironolactone, or progesterone whether HEK293T cells were transfected with either MRWT or MRS 810L . These results indicate that HDACi, but not an MR antagonist spironolactone, attenuates atypical transcriptional activity of an activating mutant MR (MRS 810L ).
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Seol-Hee
authors.initials: SH
authors.lastname: Kang
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Hae-Ahm
authors.initials: HA
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Eunjo
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Mina
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.|BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University School of Medicine, Daegu, Korea.
authors.forename: Inkyeom
authors.initials: I
authors.lastname: Kim
mesh_terms: D000450:Aldosterone / Q000494:pharmacology; D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D009154:Mutation / Q000502:physiology*; D011374:Progesterone / Q000494:pharmacology; D018161:Receptors, Mineralocorticoid / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D011374:Progesterone
keywords: HDAC inhibitor; mineralocorticoid receptor; progesterone; spironolactone; transcription