Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

Garg, Renu; Pandey, Kailash N.

doi:10.1161/01.hyp.0000051890.68573.94

Cited by 38 publications

(33 citation statements)

References 46 publications

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“…Garg and Pandey 22 reported the transcriptional downregulation of Npr1 by angiotensin (Ang) II, confirming the mutual crossregulation of the two vasoactive hormones Ang II (vasoconstrictive) and ANP (vasodilatory) in the pathway mediating the pathophysiology of hypertension. Interestingly, we recently showed that the activity of the cGMP-RE was inhibited in spontaneously hypertensive rats.…”

Section: Perspectivesmentioning

confidence: 85%

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

et al. 2004

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Abstract-Previous studies have shown that atrial natriuretic peptide (ANP) can inhibit transcription of its receptor, guanylyl cyclase A, by a mechanism dependent on cGMP and have suggested the presence of a putative cGMP-response element (cGMP-RE) in the Npr1 gene promoter. To localize and characterize the putative cis-acting element, we have subcloned a 1520-bp fragment of the rat Npr1 promoter in an expression vector containing the luciferase reporter gene. Several fragments, generated by exonuclease III-directed deletions, were transiently transfected into cells to measure their promoter activity. Deletion from Ϫ1520 to Ϫ1396 of a 1520-bp-long Npr1 promoter led to a 5-fold increase in luciferase activity. Subsequent deletion to the position Ϫ1307 resulted in a decrease of luciferase activity by 90%. Preincubation of cells with 100 nM of ANP or 100 M 8-bromo-cGMP inhibited luciferase activity of the 1520-bp and 1396-bp-long fragments, but not the activity of the 1307-bp fragment, suggesting that the cGMP-RE is localized between positions Ϫ1396 and Ϫ1307. The cGMP regulatory region was narrowed by gel shift assays and footprinting to position Ϫ1372 to Ϫ1354 from the transcription start site of Npr1 and indicated its interaction with transcriptional factor(s). Cross-competition experiments with mutated oligonucleotides led to the definition of a consensus sequence (Ϫ1372 AaAtRKaNTTCaAcAKTY Ϫ1354) for the novel cGMP-RE, which is conserved in the human (75% identity) and mouse (95% identity) Npr1 promoters. Key Words: cyclic GMP Ⅲ natriuretic peptides Ⅲ receptors, atrial natriuretic factor A trial natriuretic peptide (ANP) is a cardiac hormone with potent effects in the kidney, vasculature, and nervous system. It has vasorelaxant activity in vascular smooth muscle and promotes urinary sodium and water excretion by the kidney (for review, see Reference 1 ). These actions of ANP are brought about via the activation of membrane-bound protein, natriuretic peptide receptor type A (NPR-A), or guanylyl cyclase A. 2-4 NPR-A is a 130-KDa transmembrane protein containing an ANP-binding motif at its extracellular NH 2 terminus and GC activity at its COOH-terminal intracellular domain. 5 Activation of NPR-A leads to the conversion of GTP to the intracellular second messenger cGMP, which is involved in most of the biological responses associated with natriuretic peptides. 2-5 Increased cGMP yields receptor desensitization, resulting in a decrease of ANP-stimulated cGMP synthesis. 6 Receptor preoccupancy appears to be a mechanism of apparent receptor desensitization 7 but transfection experiments with NPR-A cDNA have revealed that early desensitization by ANP pretreatment can be due to dephosphorylation of NPR-A protein. 8 Besides, a previous study demonstrated that NPR-A activity, as well as its mRNA levels, is diminished in a time-and concentration-dependent manner by ANP or by a cell-permeable cGMP analog, 8-bromo-cGMP. 9 Those results suggest transcriptional regulation via a putative cGMPresponse element (cGMP-RE) in the p...

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Section: Perspectivesmentioning

confidence: 85%

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

et al. 2004

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“…This vitamin D-dependent induction of NPR-A expression may account for at least some of the salutary effects of vitamin D in the cardiovascular system. 71 NPR-A gene promoter activity has also been shown to be negatively regulated by angiotensin II 72 and positively regulated by osmotic stimuli. 73 The latter effect involves the endothelial NO synthase and p38 MAPK.…”

Section: Regulation Of the Np Receptorsmentioning

confidence: 99%

Molecular Biology of the Natriuretic Peptide System

et al. 2007

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T he natriuretic peptides (NPs) are a group of peptide hormones that play important roles in the control of renal, cardiovascular, endocrine, and skeletal homeostasis. Atrial NP (ANP) was first identified as an activity by de Bold et al 1 in 1981. It is a 28 amino acid peptide in humans that assumes a hairpin structure by virtue of a cystine bridge that links residues 7 and 23 ( Figure 1). Brain NP (BNP), also known as the B-type NP, is 32 amino acids long in the human. It has a similar hairpin structure but demonstrates considerably more heterogeneity across species than ANP. C-type NP (CNP) is a 22 amino acid peptide that has a truncated carboxy terminus beyond the second cystine residue in the bridge.ANP and BNP are produced primarily within the muscle cells of the heart. ANP shows a preference for expression in the cardiac atria versus ventricle, whereas BNP is more equivalently expressed throughout the heart. ANP is also expressed in the hypothalamus where it is thought to control blood pressure (BP), sympathetic outflow, vasopressin secretion, drinking behavior, and cardiovascular homeostasis. BNP, on the other hand, is expressed in the brains of only a few species (eg, pig and dog), where its function remains unknown. CNP is expressed in the central nervous system, reproductive tract, bone, and endothelium of blood vessels.There are 3 different types of NP receptors, and each of them spans the membrane bilayer as a single transmembrane segment. The type A NP receptor (NPR-A) is also known as the particulate guanylyl cyclase A. It is the high affinity receptor for both ANP and BNP. A schematic of the structure of this receptor is presented in Figure 2. NPR-A has a glycosylated, extracellular, ligand-binding domain linked to a hydrophobic transmembrane spanning segment, a noncatalytic, ATP-binding, kinase-like domain in the proximal intracellular portion of the molecule, which is thought to function as a regulator of receptor activity, and a short hinge region. The NPR-A carboxy terminus contains the particulate guanylyl cyclase that is the catalytic effector of the receptor. Association of NPR-A with its cognate ligand (ANP or BNP) causes a conformational change in the kinase-like domain, which relaxes tonic inhibition of guanylyl cyclase activity and increases production of cGMP. NPR-B shares a similar structure with NPR-A. It binds selectively to CNP. NPR-C, the so-called clearance receptor, has an extracellular domain that is structurally homologous to that of the other NPRs. This is linked to a single transmembrane-spanning segment followed by an intracellular domain containing only 37 amino acids. NPR-C binds with high affinity to all 3 NPs, as well as to a variety of other peptides with more distant structural homology. The primary role of NPR-C is to function in a clearance mode, capturing and degrading NPs in the extracellular compartment. 2 Earlier reviews have dealt with the regulators of NP gene expression. 3 This brief review will focus on the molecular details underlying the transcriptional re...

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“…105 Two recent in vitro studies have indicated that GC-A gene transcription might be inhibited by Ang II and endothelin. 106,107 It has been suggested that local endothelin production mediates the effects of changes in extracellular tonicity on GC-A expression in the kidney. 107 Again, the relevance of these experiments to the in vivo situation needs to be confirmed.…”

Section: Regulation Of Gc-a At the Level Of Gene Transcriptionmentioning

confidence: 99%

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

Kühn

2003

Circulation Research

241

161

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Abstract-Besides soluble guanylyl cyclase (GC), the receptor for NO, there are at least seven plasma membrane enzymes that synthesize the second-messenger cGMP. All membrane GCs (GC-A through GC-G) share a basic topology, which consists of an extracellular ligand binding domain, a short transmembrane region, and an intracellular domain that contains the catalytic (GC) region. Although the presence of the extracellular domain suggests that all these enzymes function as receptors, specific ligands have been identified for only three of them (GC-A through GC-C). GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure and volume homeostasis and also local antihypertrophic actions in the heart. GC-B is a specific receptor for C-type natriuretic peptide, having more of a paracrine function in vascular regeneration and endochondral ossification. GC-C mediates the effects of guanylin and uroguanylin on intestinal electrolyte and water transport and on epithelial cell growth and differentiation. GC-E and GC-F are colocalized within the same photoreceptor cells of the retina and have an important role in phototransduction. Finally, the functions of GC-D (located in the olfactory neuroepithelium) and GC-G (expressed in highest amounts in lung, intestine, and skeletal muscle) are completely unknown. This review discusses the structure and functions of membrane GCs, with special emphasis on the physiological endocrine and cardiac functions of GC-A, the regulation of hormone-dependent GC-A activity, and the relevance of alterations of the atrial natriuretic peptide/GC-A system to cardiovascular diseases. (Circ Res. 2003;93:700-709.)

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Angiotensin II–Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription

Cited by 38 publications

References 46 publications

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

Characterization of a cGMP-Response Element in the Guanylyl Cyclase/Natriuretic Peptide Receptor A Gene Promoter

Molecular Biology of the Natriuretic Peptide System

Structure, Regulation, and Function of Mammalian Membrane Guanylyl Cyclase Receptors, With a Focus on Guanylyl Cyclase-A

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