Inhibition of HDAC1 and 2 Modulates the Expression and Signaling of Natriuretic Peptide Receptor A in Male and Female Gene‐targeted Mutant Mice

Abstract

Guanylyl cyclase/natriuretic peptide receptor‐A (GC‐A/NPRA) signaling activates natriuresis, diuresis, and vasodilatation, and inhibits the cell proliferation and fibrosis. Mice lacking functional Npr1 gene (coding for GC‐A/NPRA) exhibit hypertension and kidney disorders, however, the mechanisms regulating Npr1 expression and function are not well understood. The objective of the present study was to elucidate the mechanisms of Npr1 expression and receptor function involving epigenetic regulatory mechanisms activated by class I histone deacetylase (HDAC) inhibitor, Mocetinostat (MGCD0103). Male and female (16–20 weeks old) Npr1 gene‐disrupted 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 analysis showed that MGCD0103 significantly increased the renal NPRA protein levels in Npr1+/−, Npr1+/+, and Npr1++/+ mice groups compared with vehicle‐treated controls. Female mice showed increased levels of plasma cGMP compared with male mice and treatment with MGCD0103 significantly induced cGMP levels in the drug‐treated mice groups. The renal HDAC activity and HDAC1 and 2 protein levels in male mice were higher than the corresponding female mice in all the three genotypes. MGCD0103 treatment attenuated HDAC activity by 30%‐40% and HDAC1/2 protein levels in the treated mice groups. Male and female mice showed differential acetylation levels of H3‐K9 and H3‐K27 in the renal tissues and treatment with MGCD0103 significantly enhanced the acetylation levels in the treated mice groups. Both male and female Npr1+/− mice exhibited higher systolic blood pressure (SBP) compared with the corresponding wild type Npr1+/+ mice, whereas female Npr1+/− mice exhibited significantly lower SBP than male Npr1+/− mice. A significant decrease in SBP was observed in MGCD0103‐treated male and female Npr1+/− mice. The present results suggest that MGCD0103 epigenetically regulates NPRA expression in vivo in male and female Npr1+/− mice, via inhibition of HDAC1 and 2 protein expression and histone modifications, which will have important implications in the hypertension and renal disease states.Support or Funding InformationThis work was supported by NIH grants (HL057531 and HL062147) and by an Institutional Development Award (IDeA) from the NIGMS.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.