Regulation of Blood Pressure and Renal Fibrosis by Class I Specific HDAC Inhibitor, Mocetinostat, in Npr1 Gene‐targeted Male and Female Mice

Abstract

Mice lacking Npr1 (encoding guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) exhibit hypertension, kidney disease, and heart failure; however, the epigenetic determinants regulating Npr1 expression and renal function are not well understood. The objective of this study was to investigate the effect of class I-specific histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103; MGCD) on NPRA expression and regulation of mean arterial pressure (MAP) and renal pathology. Adult male and female Npr1 haplotype (1-copy, Npr1+/-), wild-type (2-copy, Npr1+/+), and gene-duplicated (3-copy, Npr1++/+) mice were injected intraperitoneally with MGCD (2 mg/kg) at alternate days for 2-weeks. Treatment with MGCD significantly enhanced NPRA protein levels and GC activity in male and female mice in all three genotypes. MAP was monitored by telemetry recording. Sex-differences were observed in MAP as female mice had lower MAP (p < 0.01) than male mice, in all genotypes; whereas, 1-copy mice exhibited higher MAP than 2-copy mice. Treatments with MGCD distinctly reduced MAP in 1-copy and 2-copy male mice (untreated 1-copy, 125 ± 3 vs. treated 1-copy, 108 ± 3 mmHg; p < 0.001; untreated 2-copy, 98 ± 2 vs. treated 2-copy, 90 ± 2 mmHg; p < 0.01) and 1-copy and 2-copy female mice (untreated 1-copy, 117 ± 3 vs. treated 1-copy, 105 ± 2 mmHg; p < 0.001; untreated 2-copy, 90 ± 2 vs. treated 2-copy, 84 ± 2 mmHg; p < 0.01). Treatment with MGCD attenuated HDAC activity by 30% in male and 40% in female animals (p < 0.05). The Western blot analyses indicated that 1-copy male and female mice showed upregulation of alpha-smooth muscle actin (α-SMA; 39% and 29%, p < 0.05) and collagen 1 alpha 2 (COL1α2; 49% and 20%, p < 0.05) proteins, respectively, compared with 2-copy mice. Picrosirius red staining in renal sections showed significant collagen deposition in 1-copy mice compared with 2-copy animals of both sexes. MGCD reduced fibrosis by 30%-45% (p < 0.05) in treated 1-copy mice compared with untreated control mice in both sexes. The present results indicate that MGCD lowers MAP, and repairs renal fibrosis in male and female mice. These findings will have important implications for treatment of hypertension and renal injury in humans in both genders.