Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through Its Acetylation and Prevents Development of Hypertension

• Published in: Circulation research Vol. 112; no. 7; pp. 1004 - 1012
• Main Authors: Lee, Hae-Ahm, Lee, Dong-Youb, Cho, Hyun-Min, Kim, Sang-Yeob, Iwasaki, Yasumasa, Kim, In Kyeom
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 29.03.2013
• Subjects: Acetylation - drug effects; Aldosterone - pharmacology; Animals; Desoxycorticosterone - pharmacology; Disease Models, Animal; DNA Polymerase II - metabolism; Enzyme Inhibitors - pharmacology; Gene Expression - drug effects; HEK293 Cells; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Hypertension, Renal - chemically induced; Hypertension, Renal - prevention & control; Male; Mineralocorticoids - pharmacology; Nephrectomy; Promoter Regions, Genetic - genetics; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; Transcription, Genetic - drug effects; Valproic Acid - pharmacology
• DOI: 10.1161/CIRCRESAHA.113.301071
• ISSN: 0009-7330

RATIONALE:Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate–induced hypertensive rats and spontaneously hypertensive rats. However, the molecular mechanism remains elusive. OBJECTIVE:We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate–induced hypertensive rats. METHODS AND RESULTS:Expression of MR target genes was measured by quantitative real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunoprecipitation assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was determined by Western blot with anti-acetyl-lysine antibody after immunoprecipitation with anti-MR antibody. Transcriptional activity of MR was determined by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received subcutaneous injection of 40 mg/kg per week of deoxycorticosterone acetate and drinking water containing 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II on promoters of target genes. HDAC inhibition promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids. CONCLUSIONS:These results indicate that HDAC inhibition attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in deoxycorticosterone acetate–induced hypertensive rats.