Abstract
Inhibition of lysine deacetylase (KDAC) attenuated development of hypertension in spontaneously hypertensive rats (SHRs). We hypothesized that KDAC inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptors (MR) instead of histone acetylation in SHRs. Valproate (VPA, 0.71 % wt/vol), an inhibitor of class I KDACs, was administered in drinking water to 7-week-old SHRs and Wistar Kyoto rats for 11 weeks. MR acetylation was determined by immunoprecipitation with anti-MR antibody followed by western blot with anti-acetyl-lysine antibody. Expression levels of acetylated histone H3, KDACs, MR target genes, or MR corepressors in the kidney cortex were measured by using western blot analysis or real-time PCR. Recruitment of MR and RNA polymerase II (Pol II) and histone modifications on promoters of target genes were analyzed by performing a chromatin immunoprecipitation (ChIP) assay. Treatment of SHR with VPA increased MR acetylation without affecting MR expression, which attenuated development of hypertension in SHR VPA decreased expression of KDAC class I but globally increased acetylated histone H3. Although VPA treatment increased histone 3 acetylation (H3Ac) and trimethylation of the fourth lysine (H3K4me3) in the promoter regions of MR target genes, it decreased the expression of target genes as well as recruitment of MR and Pol II. These results suggest that KDAC inhibition attenuates the development of hypertension in SHRs and is accompanied by acetylation of MR that is independent of histone acetylation.
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Abbreviations
- ALDO:
-
Aldosterone
- ATP1a1:
-
Na+-K+-APTase subunit α1
- ChIP:
-
Chromatin immunoprecipitation
- EGFR:
-
Epidermal growth-factor receptor
- ENaC:
-
Epithelial Na+ channel
- GILZ:
-
Glucocorticoid-induced leucine zipper protein
- GR:
-
Glucocorticoid receptor
- HAT:
-
Histone acetyltransferase
- HRE:
-
Hormone response element
- KDAC:
-
Lysine deacetylase
- MR:
-
Mineralocorticoid receptor
- Pol II:
-
RNA polymerase II
- SGK1:
-
Serum and glucocorticoid-regulated kinase 1
- SHR:
-
Spontaneously hypertensive rats
- VPA:
-
Valproate
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Acknowledgments
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) (2013R1A1A2058145 and 2013R1A2A2A01005155), funded by the Ministry of Education, Science and Technology, and the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI13C1527).
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This investigation was conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and was approved by the Institutional Review Board of Kyungpook National University (KNU 2012–116), and every effort was made to minimize both the number of animals used and their suffering.
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The authors declare that they have no conflict of interest.
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Young Mi Seok and Hae Ahm Lee contributed equally to this work.
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Seok, Y.M., Lee, H.A., Park, K.M. et al. Lysine deacetylase inhibition attenuates hypertension and is accompanied by acetylation of mineralocorticoid receptor instead of histone acetylation in spontaneously hypertensive rats. Naunyn-Schmiedeberg's Arch Pharmacol 389, 799–808 (2016). https://doi.org/10.1007/s00210-016-1246-2
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DOI: https://doi.org/10.1007/s00210-016-1246-2