TY - JOUR T1 - All-trans Retinoic Acid and Sodium Butyrate Enhance Natriuretic Peptide Receptor A Gene Transcription: Role of Histone Modification JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.114.092221 SP - mol.114.092221 AU - Prerna Kumar AU - Ramu Periyasamy AU - Subhankar Das AU - Smitha Neerukonda AU - Indra Mani AU - Kailash N Pandey Y1 - 2014/01/01 UR - http://molpharm.aspetjournals.org/content/early/2014/04/15/mol.114.092221.abstract N2 - The objective of the present study was to delineate the mechanisms of guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) expression in vivo. We utilized all-trans retinoic acid (ATRA) and histone deacetylase (HDAC) inhibitor, sodium butyrate (NaBu) to examine the expression and function of Npr1 using gene-disrupted heterozygous (1-copy; +/-), wild-type (2-copy; +/+), and gene-duplicated heterozygous (3-copy; ++/+) mice. Npr1+/- mice exhibited increased renal HDAC and reduced histone acetyltransferase (HAT) activity; on the contrary Npr1++/+ mice showed decreased HDAC and enhanced HAT activity compared with Npr1+/+ mice. ATRA and NaBu promoted global acetylation of histones H3-K9/14 and H4-K12, reduced methylation of H3-K9 and H3-K27, and enriched accumulation of active chromatin marks at the Npr1 promoter. A combination of ATRA-NaBu promoted recruitment of activator-complex containing Ets-1, retinoic acid receptor α, and HATs (p300 and p300/CBP associated factor) at the Npr1 promoter and significantly increased renal NPRA expression, GC activity, and cGMP levels. Untreated 1-copy mice showed significantly increased systolic blood pressure (SBP) and renal expression of α-smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) compared with 2-copy and 3-copy mice. Treatment with ATRA and NaBu synergistically attenuated the expression of α-SMA and PCNA and reduced SBP in Npr1+/- mice. Our findings demonstrate that epigenetic upregulation of Npr1 gene transcription by ATRA and NaBu leads to attenuation of renal fibrotic markers and SBP in mice with reduced Npr1 gene copy number, which will have important implications in prevention and treatment of hypertension-related renal pathophysiological conditions. ER -