Hypertension and cardiovascular diseases are serious health problems for many individuals in the industrialized world. Atrial natriuretic peptide (ANP) is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and antiproliferative effects, important factors in the control of blood pressure and cardiovascular homeostasis. One of the principal loci involved in the regulatory action of ANP is the guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), whose ANP-binding and guanylyl cyclase activities vary remarkably in different tissues. However, the molecular basis of the functional expression and regulation of Npr1 gene (coding for NPRA) are not well understood. To further understand the biological role(s) played by NPRA, we will study the physiological function(s) using Npr1 gene-targeted mutant mouse models, which we have established at our facility. Our fundamental hypothesis is that the absence of Npr1 gene expression in intact animals in vivo renders unopposed powerful sodium-retaining, vasoconstrictive, proinflammatory, and proliferative systems;whereas, overexpression of Npr1 gene exerts physiological effects that are natriuretic, vasodilatory, anti-inflammatory, and antiproliferative in nature. To accomplish the objective of this proposal, we will integrate genetic information at the molecular level, with biochemical information at the cellular level, and physiological information at the whole-animal level, resulting in a vertically integrated molecular-physiological strategy. We will exploit the power of molecular genetics techniques to answer cellular, biochemical, and pathophysiological questions in intact animals in vivo so as to arrive at conclusions that are definitive and physiologically relevant. The information obtained from the above lines of investigation will provide the means to test directly the efficacy and impact of Npr1 gene dosage and null mutation on ANP/NPRA-mediated biological responses. Progress in this field of research will significantly strengthen and advance our knowledge of genetic and molecular approaches to evaluate the role of Npr1 gene in the control of fluid volume, blood pressure, congestive heart failure, and other physiological function(s) and pathological states. The resulting knowledge should yield new molecular therapeutic targets for the treatment of hypertension and prevention of hypertension-related cardiovascular disorders.

Public Health Relevance

High blood pressure is a growing problem in the modern world. More than 60 million Americans suffer from high blood pressure, which provokes kidney disease, heart failure, and stroke. Using Npr1 gene-targeted mutant mouse models, the research proposed in this application will provide new insights into the role of natriuretic peptide receptor-A in controlling blood pressure and hypertension. Moreover, this research project will elucidate the molecular mechanisms by which altered gene function may identify unique molecular targets that contribute towards the treatment and prevention of hypertension and related cardiovascular diseases. Information gained from the proposed studies will yield a more accurate assessment of the integrative and protective roles of atrial natriuretic peptide receptor gene and into possible mechanisms of pathogenesis whereby malregulation of receptor-mediated atrial natriuretic peptide bioactivity could result in abnormalities of fluid volume regulation and blood pressure homeostasis. Ultimately, this knowledge should yield new molecular therapeutic targets for the control and treatment of hypertension and cardiovascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062147-14
Application #
8452732
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
OH, Youngsuk
Project Start
1998-06-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
14
Fiscal Year
2013
Total Cost
$354,608
Indirect Cost
$118,988
Name
Tulane University
Department
Physiology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Kumar, Prerna; Periyasamy, Ramu; Das, Subhankar et al. (2014) All-trans retinoic acid and sodium butyrate enhance natriuretic peptide receptor a gene transcription: role of histone modification. Mol Pharmacol 85:946-57
Vellaichamy, Elangovan; Das, Subhankar; Subramanian, Umadevi et al. (2014) Genetically altered mutant mouse models of guanylyl cyclase/natriuretic peptide receptor-A exhibit the cardiac expression of proinflammatory mediators in a gene-dose-dependent manner. Endocrinology 155:1045-56
Zhao, Di; Das, Subhankar; Pandey, Kailash N (2013) Interactive roles of NPR1 gene-dosage and salt diets on cardiac angiotensin II, aldosterone and pro-inflammatory cytokines levels in mutant mice. J Hypertens 31:134-44
Das, Subhankar; Periyasamy, Ramu; Pandey, Kailash N (2012) Activation of IKK/NF-?B provokes renal inflammatory responses in guanylyl cyclase/natriuretic peptide receptor-A gene-knockout mice. Physiol Genomics 44:430-42
Pandey, Kailash N (2011) The functional genomics of guanylyl cyclase/natriuretic peptide receptor-A: perspectives and paradigms. FEBS J 278:1792-807
Pandey, Kailash N (2011) Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation. Can J Physiol Pharmacol 89:557-73
Das, Subhankar; Au, Edward; Krazit, Stephen T et al. (2010) Targeted disruption of guanylyl cyclase-A/natriuretic peptide receptor-A gene provokes renal fibrosis and remodeling in null mutant mice: role of proinflammatory cytokines. Endocrinology 151:5841-50
Zhao, Di; Pandey, Kailash N; Navar, L Gabriel (2010) ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor. Am J Physiol Renal Physiol 298:F103-8
Kumar, Prerna; Garg, Renu; Bolden, Gevoni et al. (2010) Interactive roles of Ets-1, Sp1, and acetylated histones in the retinoic acid-dependent activation of guanylyl cyclase/atrial natriuretic peptide receptor-A gene transcription. J Biol Chem 285:37521-30
Pandey, Kailash N; Vellaichamy, Elangovan (2010) Regulation of cardiac angiotensin-converting enzyme and angiotensin AT1 receptor gene expression in Npr1 gene-disrupted mice. Clin Exp Pharmacol Physiol 37:e70-7

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