Abstract 034: Differential Regulation of Renal Injury in Npr1 Gene-Targeted Male and Female Mice: Role of Class I-Specific HDAC Inhibitor

Abstract

The objective of the present study was to gain insight into the effect of class I-specific histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103; MGCD) on Npr1 (coding for natriuretic peptide receptor-A; NPRA) gene expression and regulation of 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. The renal NPRA protein levels were significantly increased in the treated male (1-copy, 2.1-fold; 2-copy, 2.3-fold; and 3-copy, 1.5-fold; p < 0.05) and female mice (1-copy, 3.6-fold; 2-copy, 2.1-fold; and 3-copy, 1.7-fold; p < 0.05) compared with untreated animals. After MGCD treatment, the renal guanylyl cyclase-A (GC-A) activity significantly increased in male mice (1-copy, 77.4 ± 0.5 vs. control 30.7 ± 0.5; 2-copy 126.1 ± 5.0 vs. control 76.3 ± 6.3; and 3-copy, 182.7 ± 2.8 vs. control 141.2 ± 6.4; p < 0.05; cGMP/mg protein/ 30 min) and female mice (1-copy, 108.2 ± 6.8 vs. control 51.9 ± 3.0; p < 0.05). Male mice exhibited significantly higher systolic blood pressure (SBP) than females and treatment with MGCD decreased SBP in both 1-copy male (106 ± 0.6 vs. control, 129 ± 1.9; mmHg) and female mice (97 ± 2.2 vs. control, 110 ± 2.1, p < 0.001). Higher urinary albumin to creatinine ratio was detected in male mice compared with female mice, which was attenuated by MGCD treatment in male mice (1-copy, 0.39 ± 0.04 vs. untreated 0.71 ± 0.05; 2-copy 0.31 ± 0.01 vs. untreated 0.46 ± 0.05; and 3-copy, 0.2 ± 0.02 vs. untreated 0.21 ± 0.02; p < 0.05). HDAC activity was significantly higher in male mice (1-copy, 24.4 ± 2.8; 2-copy, 15.9 ± 1.2; and 3-copy, 6.4 ± 0.7; ng/min/mg protein) than female mice (1-copy, 13.7 ± 1.4; 2-copy, 8.5 ± 0.9; and 3-copy, 4.7 ± 0.9, p < 0.05); however, MGCD treatment significantly attenuated HDAC activity in both male and female animals (p < 0.05). The present results indicate MGCD upregulates Npr1 expression in 1-copy haplotype mice via inhibition of HDAC activity, lowers SBP and repairs renal injury differentially in male vs. female mice. These findings will have important implications for treatment of hypertension and renal injury in humans in a sex-related manner.