All-Trans Retinoic Acid and Sodium Butyrate Enhance Natriuretic Peptide Receptor A Gene Transcription: Role of Histone Modification

Abstract

The objective of the present study was to delineate the mechanisms of GC-A/natriuretic peptide receptor-A (GC-A/ NPRA) gene (Npr1) expression in vivo. We used 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; 1/2), wild-type (2-copy; 1/1), and gene-duplicated heterozygous (3-copy; 11/1) mice. Npr1 1/2 mice exhibited increased renal HDAC and reduced histone acetyltransferase (HAT) activity; on the contrary, Npr111/1 mice showed decreased HDAC and enhanced HAT activity compared with Npr1 1/1 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 E26 transformation-specific 1, retinoic acid receptor a, and HATs (p300 and p300/cAMP response element-binding protein-binding protein-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 and renal expression of a-smooth muscle actin (a-SMA) and proliferating cell nuclear antigen (PCNA) compared with 2-and 3-copy mice. Treatment with ATRA and NaBu synergistically attenuated the expression of a-SMA and PCNA and reduced systolic blood pressure in Npr1 1/2 mice. Our findings demonstrate that epigenetic upregulation of Npr1 gene transcription by ATRA and NaBu leads to attenuation of renal fibrotic markers and systolic blood pressure in mice with reduced Npr1 gene copy number, which will have important implications in prevention and treatment of hypertension-related renal pathophysiological conditions.

Retinoic acid and sodium butyrate suppress the cardiac expression of hypertrophic markers and proinflammatory mediators in Npr1 gene-disrupted haplotype mice

“…The balance between HAT and HDAC is an essential regulatory switch, which can be achieved through the inhibition of the deacetylation process (17,51). Our previous studies have also demonstrated that Npr1 gene contains various cis-acting elements and both RA and SB enhance its gene transcription and expression (30). Treatment with HB significantly induced cardiac NPRA expression in Npr1 ϩ/Ϫ mice.…”

“…Moreover, mixed esters of butyric acid and retinoic acid hybrid drug (HB) have also been reported to enhance cardiac repair of infarcted hearts in the experimental animals (61,70). In the present study, we examined the effect of RA-, SB-, and HB-mediated effects on the study (30). Control groups were injected with vehicle (DMSO and olive oil).…”

Angiotensin II represses Npr1 expression and receptor function by recruitment of transcription factors CREB and HSF-4a and activation of HDACs

“…Primers for amplification of Npr1 and β-actin were from Qiagen. PCR amplification was done in triplicate in a 25-µl reaction volume using RT 2 Real-Time SYBR Green/ROX PCR Master Mix and PCR conditions as previously described 78 . Control experiments were done with RNA samples but without reverse transcriptase.…”

Regulation of IgA Class Switch Recombination in Immunoglobulin A Nephropathy: Retinoic Acid Signaling and BATF

“…Because of high lipophilicity, ATRA is thought to be responsible for the slow dissolution and low bioavailability following oral administration [51] , so ATRA (500 μg/kg body weight) was dosed intraperitoneally. This dose of ATRA was selected on the basis of existing data [52,53] . In vivo, retinol is the major source of RA and RALDH is identified as an RA-generating enzyme [54] .…”