Regulation of Natriuretic Peptide Receptor‐A Expression in Gene‐targeted Mice via Modulation of Histone 3 Acetylation and Methylation Levels

Abstract

Guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) signaling plays a well‐defined role in the regulation of blood pressure and blood volume. Mice lacking functional Npr1 gene (coding for GC‐A/NPRA) exhibit hypertension, kidney disease, and heart failure; however, the mechanisms regulating Npr1 expression are not well understood. The objective of the present study was to determine the effect of class I histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103) on the expression of Npr1 via modulation of epigenetic changes. Male and female (16–20 weeks old) Npr1 gene‐knockout heterozygous (1‐copy; Npr1+/−), wild‐type (2‐copy; Npr1+/+) and gene‐duplicated heterozygous (3‐copy; Npr1++/+) mice were injected intraperitoneally with MGCD0103 (2 mg/kg) at alternate days for 2‐weeks. The Western blot result showed that MGCD0103 significantly increased the renal NPRA protein levels in male and female mice compared with vehicle‐treated controls. Plasma cGMP levels were higher in female mice compared with male mice both before and after the treatment with MGCD0103. Renal HDAC activity was significantly higher (p < 0.05) in male mice than female mice; however, treatment with MGCD0103 significantly attenuated (p < 0.05) HDAC activity by 40% in male and ~50% in female animals. The histone acetyltransferase (HAT) activity was lower in untreated 1‐copy male mice compared with wild‐type mice and MGCD0103 treatment significantly increased HAT activity whereas no significant differences were observed in drug‐or vehicle‐treated female mice. Male and female mice showed differential renal acetylation levels of histone 3 at different lysine positions (H3‐K9, H3‐K18, and H3‐K27) and treatment with MGCD0103 significantly enhanced the acetylation levels of H3‐K9 and H3‐K27 in 1‐copy male mice and H3‐K18 in 1‐copy female mice. There was substantial decrease in methylation of suppressive histone marks (H3‐K9 and H3‐K27) in MGCD0103‐treated 1‐copy male and female mice. Male mice exhibited significantly higher systolic blood pressure (SBP) than female mice and treatment with MGCD0103 decreased SBP in both 1‐copy male (106 ± 0.6 vs. vehicle‐treated, 129 ± 1.9; mmHg) and female (97 ± 2.2 vs. vehicle‐treated, 110 ± 2.1 mmHg, p < 0.001) mice. The present results provide direct evidence that MGCD0103 epigenetically regulates NPRA expression in vivo in 1‐copy male and female haplotype mice, via attenuation of HDAC activity and increase in histone H3 acetylation levels. These findings will have important implications in prevention and treatment of hypertension and renal pathophysiological conditions under reduced NPRA signaling.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147) and a partial support from Tulane Carol Lavin Bernick grant award.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.