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Class I‐Specific HDAC Inhibitor Stimulates the Expression of Npr1 in Haplotype Mice by Enhanced Histone Acetylation at Different Lysine Residues
Author(s) -
Kumar Prerna,
Gogulamudi Venkateshwara R.,
Nguyen Christian,
Pandey Kailash N.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.755.8
Subject(s) - histone h3 , acetylation , histone deacetylase , hdac3 , histone , endocrinology , medicine , biology , microbiology and biotechnology , chemistry , biochemistry , gene
Guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) signaling activates natriuresis/diuresis, vasodilatation, and inhibits the cell proliferation and fibrosis. The objective of the present study was to gain insight into the mechanisms of Npr1 (coding for GC‐A/NPRA) expression and receptor function involving epigenetic regulatory mechanisms activated by class I histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103). We utilized 20‐ to 22‐weeks old male Npr1 gene‐knockout haplotype (1‐copy; Npr1 +/− ), wild‐type (2‐copy; Npr1 +/+ ) and gene‐duplicated heterozygous (3‐copy; Npr1 ++/+ ) mice. The mice were injected intraperitonealy with MGCD0103 (5 mg/kg) at the alternate days for 2‐weeks. The Western blot analysis showed that MGCD0103 significantly increased the renal NPRA mRNA and protein levels in all mice groups compared with vehicle‐treated controls. There was marked increase in renal cGMP levels in MGCD0103‐treated mice groups. The Npr1 haplotype mice exhibited increased HDAC activity and decreased acetylated histone levels; however, 3‐copy mice showed lower HDAC activity compared with 2‐copy mice. Treatment with MGCD0103 significantly attenuated HDAC activity by almost 50% in Npr1 haplotype mice. A substantial global increase in acetylation levels of histone 3 at different lysine positions (H3‐K9/14ac, H3‐K18ac, and H3‐K27ac) and histone 4 lysine 8 (H4‐K8ac) was observed in the kidneys of MGCD0103‐treated mice. The present results suggest that MGCD0103 epigenetically regulates NPRA expression in vivo via HDAC inhibition and histone modifications, which might have important implications in the renal function in disease states. Support or Funding Information This work was supported by NIH grants (HL057531 and HL062147) and by an Institutional Development Award (IDeA) from the NIGMS.