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

Abstract

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.

Keywords: cGMP; cardiovascular hemostasis; gene-targeting; hypertension; natriuretic peptide receptor; receptor signaling.

Fig. 1.

Diagrammatic representation of ligand-dependent activation and physiological functions of NPRA, NPRB, and NPRC. ANP-binding activates NPRA, which leads to enhanced production of second messenger cGMP with stimulation and activation of ANP-dependent cellular and physiological responsiveness. CNP activates NPRB, and all three NPs activate NPRC. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; LBD, ligand binding domain; TM, transmembrane domain; KHD, kinase like homology domain; DD, dimerization domain; GCD, guanylyl cyclase catalytic domain; IP₃, inositol trisphosphate.

Fig. 2.

Effect of volume expansion on mean blood pressures in Npr1 homozygous mutant and gene-duplicated mice. Mean blood pressures by cannulated carotid arterial methods were continuously recorded for 160 min throughout the duration of the experiment. **P < 0.01; ***P < 0.001. The figure has been reproduced and adapted with permission from Shi et al. (203).

Fig. 3.

Diagrammatic representation of the Npr1 gene-disruption on renal remodeling, and blood pressure. Disruption of Npr1 gene leads to impaired renal functions, which triggers specific structural and molecular changes in 0-copy mice kidney. Activated inhibitory kappa kinase (IKK) induces the phosphorylation of IκBα, which then undergoes enzymatic degradation. The reduction of cytosolic IκBα favors the constitutive activation of NF-κB, which translocates into the nucleus and activates the transcription of proinflammatory cytokines and extracellular matrix protein genes in the kidneys of Npr1 gene-disrupted mice. These molecular changes lead to increase in the inflammatory responses and high blood pressure in Npr1 gene-disrupted mutant mice.

Fig. 4.

Defective ANP-BNP/NPRA signaling could provoke renal, cardiac, and vascular dysfunction. The defects in ANP-BNP/NPRA signaling cascade are usually associated with hypertension, heart failure, vascular disease, and metabolic syndrome. Thus, defective ANP-BNP/NPRA/cGMP signaling could lead to renal, cardiac, and vascular dysfunction.