Abstract P161: Inhibition of Class I HDAC Enhances the Expression of Npr1 and Repairs Renal Pathology in Gene-targeted Haplotype Mice

Abstract

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 (coding for natriuretic peptide receptor-A; NPRA) and renal pathology in Npr1 gene-disrupted haplotype (50% of normal) mice. Adult male Npr1 haplotype (1-copy; Npr1 +/- ), wild-type (2-copy; Npr1 +/+ ), and gene-duplicated (3-copy; Npr1 ++/+ ) mice were injected intraperitonealy with MGCD0103 (2 mg/kg) at alternate days for 2-weeks. After MGCD0103 treatment, the renal Npr1 mRNA was increased in Npr1 +/- mice by 7.3-fold (p < 0.01), Npr1 +/+ mice by 4.4-fold (p < 0.05) and Npr1 ++/+ mice by 3.6-fold (p < 0.05) compared with vehicle-treated controls. The MGCD0103 also enhanced renal cGMP levels (pmol/mg protein) in Npr1 +/- (57 ± 7 vs. control, 12 ± 1; p < 0.01), Npr1 +/+ (125 ± 9 vs. control, 66 ± 5; p < 0.01), and Npr1 ++/+ (202 ± 7 vs. control, 127 ± 15; p < 0.05) mice. An increased HDAC activity (ng/min/mg protein) was observed in Npr1 +/- mice (24.4 ± 2.8; p < 0.05); however, Npr1 ++/+ mice showed lower HDAC activity (6.4 ± 0.7; p < 0.05); compared with Npr1 +/+ mice (15.9 ± 1.3). Treatment with MGCD0103 significantly attenuated HDAC activity by almost 50% (15.3 ± 1.2; p < 0.01) in Npr1 haplotype mice. A significant decrease in systolic blood pressure was observed in MGCD0103-treated Npr1 +/- mice (106 ± 0.6 vs. control, 131 ± 1.9, p < 0.001). Significantly lower creatinine clearance (μl/min) was observed in Npr1 +/- (51 ± 11; p < 0.05) vs. Npr1 +/+ mice (130 ± 14.0; p < 0.05) and treatment with MGCD0103 increased creatinine clearance in Npr1 +/- mice (105 ± 13; p < 0.05) vs. controls. Higher urinary albumin to creatinine ratio was detected in Npr1 +/- mice (0.7 ± 0.05) vs. Npr1 +/+ animals (0.5 ± 0.05; p < 0.05) and a complete reversal was observed in drug-treated Npr1 +/- mice (0.4 ± 0.04). The present results provide direct evidence that class I HDAC inhibition upregulates NPRA expression in vivo and repairs the renal pathology in Npr1 +/- haplotype mice. The present findings will have important implications in the treatment and prevention of hypertension and renal pathophysiological conditions.