Genetic disruption of guanylyl cyclase/natriuretic peptide receptor-A upregulates ACE and AT1 receptor gene expression and signaling: role in cardiac hypertrophy

2007 ◽  
Vol 31 (2) ◽  
pp. 193-202 ◽  
Author(s):  
Elangovan Vellaichamy ◽  
Di Zhao ◽  
Naveen Somanna ◽  
Kailash N. Pandey
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Heart Weight ◽  
Natriuretic Peptide Receptor ◽  
Wild Type ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Npr1 Gene

Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) signaling antagonizes the physiological effects mediated by the renin-angiotensin system (RAS). The objective of this study was to determine whether the targeted-disruption of Npr1 gene (coding for GC-A/NPRA) leads to the activation of cardiac RAS genes involved on the hypertrophic remodeling process. The Npr1 gene-knockout ( Npr1 −/−) mice showed 30–35 mmHg higher systolic blood pressure (SBP) and a 63% greater heart weight-to-body weight (HW/BW) ratio compared with wild-type ( Npr1 +/+) mice. The mRNA levels of both angiotensin-converting enzyme and angiotensin II type 1a receptor were increased by three- and fourfold, respectively, in Npr1 −/− null mutant mice hearts compared with the wild-type Npr1 +/+ mice hearts. In parallel, the expression levels of interleukin-6 and tumor necrosis factor-α were increased by four- to fivefold, in Npr1 −/− mice hearts compared with control animals. The NF-κB binding activity in nuclear extracts of Npr1 −/− mice hearts was increased by fourfold compared with wild-type Npr1 +/+ mice hearts. Treatments with captopril or hydralazine equally attenuated SBP; however, only captopril significantly decreased the HW/BW ratio and suppressed cytokine gene expression in Npr1 −/− mice hearts. The ventricular cGMP level was reduced by almost sixfold in Npr1 −/− mice compared with wild-type control mice. The results of the present study indicate that disruption of NPRA/cGMP signaling leads to the augmented expression of cardiac RAS pathways that promote the development of cardiac hypertrophy and remodeling.

scholarly journals Molecular and genetic aspects of guanylyl cyclase natriuretic peptide receptor-A in regulation of blood pressure and renal function

2018 ◽  
Vol 50 (11) ◽  
pp. 913-928 ◽  
Author(s):  
Kailash N. Pandey
Keyword(s):  
Blood Pressure ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Natriuretic Peptides ◽  
Molecular Mechanisms ◽  
Phenotypic Characterization ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A ◽  
Regulation Of Blood Pressure

Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.

Genetic disruption of atrial natriuretic peptide receptor-A alters renin and angiotensin II levels

2001 ◽  
Vol 281 (4) ◽  
pp. F665-F673 ◽  
Author(s):  
Shang-Jin Shi ◽  
Huong T. Nguyen ◽  
Guru Dutt Sharma ◽  
L. Gabriel Navar ◽  
Kailash N. Pandey
Keyword(s):  
Natriuretic Peptide ◽  
Systolic Arterial Pressure ◽  
Inhibitory Response ◽  
Mutant Mice ◽  
Natriuretic Peptide Receptor ◽  
Ang Ii ◽  
Wild Type ◽  
Compensatory Response ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A

We have studied cardiovascular and renal phenotypes in Npr1 (genetic determinant of natriuretic peptide receptor-A; NPRA) gene-disrupted mutant mouse model. The baseline systolic arterial pressure (SAP) in 0-copy mutant (−/−) mice (143 ± 2 mmHg) was significantly higher than in 2-copy wild-type (+/+) animals (104 ± 2 mmHg); however, the SAP in 1-copy heterozygotes (+/−) was at an intermediate value (120 ± 4 mmHg). To determine whether Npr1 gene function affects the renin-angiotensin-aldosterone system (RAAS), we measured the components of RAAS in plasma, kidney, and adrenal gland of 0-copy, 1-copy, and 2-copy male mice. Newborn (2 days after the birth) 0-copy pups showed 2.5-fold higher intrarenal renin contents compared with 2-copy wild-type counterparts (0-copy 72 ± 12 vs. 2-copy 30 ± 7 μg ANG I · mg protein−1 · h−1, respectively). The intrarenal ANG II level in 0-copy pups was also higher than in 2-copy controls (0-copy 33 ± 5 vs. 2-copy 20 ± 2 pg/mg protein, respectively). However, both young (3 wk) and adult (16 wk) 0-copy mutant mice showed a dramatic 50–80% reduction in plasma renin concentrations (PRCs) and in expression of renal renin message compared with 2-copy control animals. In contrast, the adrenal renin content and mRNA expression levels were 1.5- to 2-fold higher in 0-copy adult mice than in 2-copy animals. The results suggest that inhibition of renal and systemic RAAS is a compensatory response that prevents greater increases in elevated arterial pressures in adult NPRA null mutant mice. However, the greater renin and ANG II levels seen in 0-copy newborn pups provide evidence that the direct effect of NPRA activation on renin is an inhibitory response.

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