Abstract 134: Role Of Epigenetic Mechanisms Regulating Renal Pathology And Disorders In Global Npr1 Gene-targeted Mutant Mice In Sex-dependent Manner

Abstract

The objective of this study was to investigate the effect of class I-specific histone deacetylase inhibitor, mocetinostat (MGCD0103; MGCD) in the regulation of epigenetic mechanisms and renal pathology and disorders in Npr1 (coding for natriuretic peptide receptor A; NPRA) gene-disrupted haplotype mice. Male and female Npr1 gene-disrupted (1-copy; +/- ), wild-type (2-copy; +/+ ) and gene-duplicated (3-copy; ++/+) mice were administrated with MGCD (2 mg/kg) by intraperitoneal injection at alternate days for 2-weeks. The renal NPRA protein levels and guanylyl cyclase (GC) activity were significantly lower in 1-copy mice and higher in 3-copy than in 2-copy mice; however, MGCD increased NPRA protein levels and GC activity. The vehicle-treated females showed lower SBP than male mice, whereas both sexes of 1-copy mice had higher SBPs, and 3-copy mice had lower SBPs as compared with 2-copy mice. Treatment with MGCD distinctly reduced SBP in male (1-copy, Δ-21±2.0 mmHg, p<0.001; 2-copy, Δ-5±0.6 mmHg, p<0.01; and 3-copy, Δ-4±0.5 mmHg, p<0.05) and female mice (1-copy, Δ-17±2.1 mmHg, p<0.01; 2-copy, Δ-3±0.5 mmHg, p<0.01; and 3-copy, Δ-3±0.8 mmHg). Hematoxylin and eosin staining showed pronounced renal morphological damages in 1-copy male than female mice as compared to 2-copy and 3-copy mice. One-copy male mice exhibited a greater degree of mesangial matrix expansion and interstitial nephritis as compared with 2-copy and 3-copy mice, which was significantly (p<0.1) decreased with MGCD treatment as compared with vehicle-treated mice. Creatinine clearance was significantly reduced in 1-copy male mice (52%; p<0.05) than female mice (35%; p<0.05) compared with 2-copy mice. The renal HDAC activity and HDAC1 and 2 protein levels in 1-copy male mice were significantly (p<0.05) higher than female mice as compared with 2-copy mice. MGCD markedly increased acetylation of histone marks (H3-K9, H3-K27, and H3-K18) and greatly reduced the renal pathologies as compared with controls. The present results demonstrate that MGCD upregulates NPRA activity and repairs renal pathology epigenetically in 1-copy haplotype mice. These findings will have important implications for treatment of hypertension and renal injury in humans in both sexes.