Kailash N Pandey
Tulane University, USA
Title: Regulation of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Gene Expression and Signaling: Interactive Roles of Histone Modifications and Transcription Factors
Biography
Biography: Kailash N Pandey
Abstract
The mechanisms regulating high blood pressure are known to have a strong genetic component; however, the specific genes involved in the pathogenesis of hypertension are not well defined. A key regulators are atrial and brain natriuretic peptides (ANP, BNP), signaling through guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and the second messenger cGMP. Currently, the mechanisms regulating the transcriptional activation and functional expression of Npr1 (coding for GC-A/NPRA) and receptor signaling are not well understood. To delineate the mechanisms of transcriptional regulation and expression of Npr1 and receptor signaling, we determined the interactive roles of all-trans retinoic acid (ATRA), transcription factors (Ets-1, SP-1), and histone deacetylases (HDACs). Deletional analysis of Npr1 promoter, luciferase assay, and chromatin immunoprecipitation indicated that ATRA dramatically enhanced Npr1 promoter activity in a time- and dose-dependent manner in primary cells in vitro and kidneys of intact animals in vivo. The transcriptional stimulation of Npr1 enhanced the guanylyl cyclase (GC) activity of receptor and the intracellular accumulation of second messenger cGMP; however, subsequently suppressed the expression of proinflammatory and fibrotic genes in the hypertensive haplotype (Npr1+/-) mice. The chromatin immunoprecipitation analysis indicated that the binding of Ets-1 and Sp1 to Npr1 promoter recruited p300 to form a transcriptional co-activation complex and increased the acetylation of histones H3 and H4. In contrast, Npr1 promoter embodying transcription factor delta-crystalline enhancer binding factor-1 (δEF-1) exhibited a repressive effect on Npr1 transcription in response to transforming growth factor-beta 1 (TGF-β1). Our results have provided the evidence that stimulatory molecule ATRA upregulated Npr1 transcription and receptor signaling by recruitment of Sp1, Ets-1, and p300 complex to Npr1 promoter in the disease state. On the contrary, TGF-β1 repressed the Npr1 transcription and receptor signaling, including decrease in GC activity and intracellular accumulation of cGMP and subsequent increase in proinflammatory and fibrotic markers. Our findings are significant for understanding the functional roles of Npr1 and receptor signaling for possible molecular therapeutic targets in the treatment and prevention of hypertension and cardiovascular diseases.