Regulation of ANP Receptor Activity in Vascular Cells

University Of California San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by the applicant): The natriuretic peptides play an important role in the regulation of cardiovascular and renal homeostasis. They bind with high affinity to surface receptors present on target cells and initiate a series of signal transduction events that, in the whole animal, result in reductions in blood pressure and an increase in renal excretion of sodium and water. There are three natriuretic peptide receptors, NPR-A, -B and -C. NPR-A binds to two cardiac hormones, atrial and brain natriuretic peptide (ANP and BNP, respectively) while NPR-B associates predominantly with the C-type natriuretic peptide (CNP) which is produced in the nervous system, reproductive tract and endothelium. NPR-C, the so-called clearance receptor, is expressed in a wide variety of tissues. While it may possess independent signaling activity, it is primarily responsible for sequestering NPs from the extracellular space. While a large body of information exists regarding the signal transduction activity associated with these receptors and the physiological role that each plays in the whole animal, very little information is available regarding their regulation, particularly at a transcriptional level. We have shown previously that expression of the NPR-A gene is controlled by three Sp1 sites and a single NF-Y site in the proximal promoter of that gene. We have also shown that the gene is down regulated by the receptor ligand ANP and upregulated by increases in extracellular tonicity and a number of nuclear receptor ligands, including vitamin D and retinoic acid. In the present application, we will attempt to determine the transcriptional regulatory controls that govern expression of the human NPR-B gene. Both the cis-acting regulatory elements and the trans-acting proteins that associate with them will be explored in detail. We have cloned and sequenced approximately 6 kb of 5'-flanking sequence from this gene as a prelude to these studies. We will also investigate the mechanism(s) underlying suppression of NPR-B and NPR-C gene expression by glucocorticoids and activation of NPR-A by 1,25-dihydroxyvitamin D and extracellular tonicity in relevant target cell or whole animal models. Collectively, these studies should define the transcriptional regulatory control of these important genes in detail and add significantly to our understanding of their respective roles in the maintenance of cardiovascular and renal homeostasis.