Regulation of guanylyl cyclase/natriuretic peptide receptor-A gen | 48787

Journal of Neuroscience and Neuropharmacology

Regulation of guanylyl cyclase/natriuretic peptide receptor-A gene expression and signaling: Interactive roles of histone modifications and transcription factors

4th Global Experts Meeting on Neuropharmacology

September 14-16, 2016 San Antonio, USA

Kailash N Pandey

Tulane University, USA

Scientific Tracks Abstracts: Neurochem Neuropharm

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 pro-inflammatory 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 (├?┬┤EF-1) exhibited a repressive effect on Npr1 transcription in response to transforming growth factor-beta 1 (TGF-├?┬▓1). 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-├?┬▓1 repressed the Npr1 transcription and receptor signaling, including decrease in GC activity and intracellular accumulation of cGMP and subsequent increase in pro-inflammatory 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.

Biography :

Kailash N Pandey is a Professor and Vice Chair in the Department of Physiology, Tulane University. He has completed MSc from Kanpur University, India, and PhD from University of Kentucky, Lexington in 1979. He has completed his Post-doctoral at Vanderbilt University and subsequently was promoted to a Faculty. In 1990, he moved to Medical college of Georgia and in 1997 he joined the Tulane University, School of Medicine. The research in his laboratory has focused on atrial natriuretic peptide (ANP) and guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA)-mediated regulation of blood pressure and cardiovascular homeostasis. His laboratory deduced the amino acid sequence of murine GC-A/NPRA and genomic sequence of Npr1 (coding for GC-A/NPRA). He has published 106 research articles, 21 book chapters and 221 abstracts. He has been a Special Guest Editorship of the journal of Peptides, and Editorship of one book. Currently, he is on the Editorial Board of 6 journals and serves as a reviewer of several NIH and AHA study sections.