scholarly journals Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A

2013 ◽  
Vol 114 (3) ◽  
pp. 307-315 ◽  
Author(s):  
James R. Klinger ◽  
Shu-Whei Tsai ◽  
Sabrina Green ◽  
Katie L. Grinnell ◽  
Jason T. Machan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Atrial Natriuretic Peptide ◽  
Pulmonary Edema ◽  
Natriuretic Peptide ◽  
Protein Concentration ◽  
Natriuretic Peptide Receptor ◽  
Edema Formation ◽  
Peptide Receptor ◽  
Cell Counts ◽  
Natriuretic Peptide Receptor A

Atrial natriuretic peptide (ANP) inhibits agonist-induced pulmonary edema formation, but the signaling pathway responsible is not well defined. To investigate the role of the particulate guanylate cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A), we measured acute lung injury responses in intact mice and pulmonary microvascular endothelial cells (PMVEC) with normal and disrupted expression of NPR-A. NPR-A wild-type (NPR-A+/+), heterozygous (NPR-A+/−), and knockout (NPR-A−/−) mice were anesthetized and treated with thrombin receptor agonist peptide (TRAP) or lipopolysaccharide (LPS). Lung injury was assessed by lung wet-to-dry (W/D) weight and by protein and cell concentration of bronchoalveolar lavage (BAL) fluid. No difference in pulmonary edema formation was seen between NPR-A genotypes under baseline conditions. TRAP and LPS increased lung W/D weight and BAL fluid cell counts more in NPR-A−/− mice than in NPR-A+/− or NPR-A+/+ mice, but no genotype-related differences were seen in TRAP-induced increases in bloodless lung W/D weight or LPS-induced increases in BAL protein concentration. Pretreatment with ANP infusion completely blocked TRAP-induced increases in lung W/D weight and blunted LPS-induced increases in BAL cell counts and protein concentration in both NPR-A−/− and NPR-A+/+ mice. Thrombin decreased transmembrane electrical resistance in monolayers of PMVECs in vitro, and this effect was attenuated by ANP in PMVECs isolated from both genotypes. Administration of the NPR-C-specific ligand, cANF, also blocked TRAP-induced increases in lung W/D weight and LPS-induced increases in BAL cell count and protein concentration in NPR-A+/+ and NPR-A−/− mice. We conclude that ANP is capable of attenuating agonist-induced lung edema in the absence of NPR-A. The protective effect of ANP on agonist-induced lung injury and pulmonary barrier function may be mediated by NPR-C.

The role of natriuretic peptide receptor-A signaling in unilateral lung ischemia-reperfusion injury in the intact mouse

2008 ◽  
Vol 294 (4) ◽  
pp. L714-L723 ◽  
Author(s):  
Jeffrey M. Dodd-o ◽  
Maria L. Hristopoulos ◽  
Kathleen Kibler ◽  
Jolanta Gutkowska ◽  
Suhayla Mukaddam-Daher ◽  
...  
Keyword(s):  
Lung Injury ◽  
Natriuretic Peptide ◽  
Ischemia Reperfusion ◽  
Intracellular Camp ◽  
Natriuretic Peptide Receptor ◽  
Intact Mouse ◽  
Peptide Receptor ◽  
Natriuretic Peptide Receptor A

Ischemia-reperfusion (IR) causes human lung injury in association with the release of atrial and brain natriuretic peptides (ANP and BNP), but the role of ANP/BNP in IR lung injury is unknown. ANP and BNP bind to natriuretic peptide receptor-A (NPR-A) generating cGMP and to NPR-C, a clearance receptor that can decrease intracellular cAMP. To determine the role of NPR-A signaling in IR lung injury, we administered the NPR-A blocker anantin in an in vivo SWR mouse preparation of unilateral lung IR. With uninterrupted ventilation, the left pulmonary artery was occluded for 30 min and then reperfused for 60 or 150 min. Anantin administration decreased IR-induced Evans blue dye extravasation and wet weight in the reperfused left lung, suggesting an injurious role for NPR-A signaling in lung IR. In isolated mouse lungs, exogenous ANP (2.5 nM) added to the perfusate significantly increased the filtration coefficient sevenfold only if lungs were subjected to IR. This effect of ANP was also blocked by anantin. Unilateral in vivo IR increased endogenous plasma ANP, lung cGMP concentration, and lung protein kinase G (PKGI) activation. Anantin enhanced plasma ANP concentrations and attenuated the increase in cGMP and PKGI activation but had no effect on lung cAMP. These data suggest that lung IR triggered ANP release and altered endothelial signaling so that NPR-A activation caused increased pulmonary endothelial permeability.

scholarly journals Subcellular trafficking of guanylyl cyclase/natriuretic peptide receptor-A with concurrent generation of intracellular cGMP

2015 ◽  
Vol 35 (5) ◽  
Author(s):  
Indra Mani ◽  
Renu Garg ◽  
Satyabha Tripathi ◽  
Kailash N. Pandey
Keyword(s):  
Blood Pressure ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Fluid Volume ◽  
Natriuretic Peptide Receptor ◽  
Subcellular Trafficking ◽  
Peptide Receptor ◽  
Intracellular Cgmp ◽  
Natriuretic Peptide Receptor A

Atrial natriuretic peptide (ANP) modulates blood pressure and fluid volume by activation of natriuretic peptide receptor-A (NPRA). Immunofluorescence (IF) studies reveal that NPRA is internalized and redistributed into subcellular compartments with concurrent production of cGMP.

Dynamics of internalization and sequestration of guanylyl cyclase/atrial natriuretic peptide receptor-A

2001 ◽  
Vol 79 (8) ◽  
pp. 631-639 ◽  
Author(s):  
Kailash N Pandey
Keyword(s):  
Plasma Membrane ◽  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Guanylyl Cyclase ◽  
Culture Media ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Receptor Complexes ◽  
Natriuretic Peptide Receptor A ◽  
Atrial Natriuretic

The guanylyl cyclase/natriuretic peptide receptor-A (NPRA), also referred to as GC-A, is a single polypeptide molecule. In its mature form, NPRA resides in the plasma membrane and consists of an extracellular ligand-binding domain, a single transmembrane-spanning region, and intracellular cytoplasmic domain that contains a protein kinase-like homology domain (KHD) and a guanylyl cyclase (GC) catalytic active site. The binding of atrial natriuretic peptide (ANP) to NPRA occurs at the plasma membrane; the receptor is synthesized on the polyribosomes of the endoplasmic reticulum, and is presumably degraded within the lysosomes. It is apparent that NPRA is a dynamic cellular macromolecule that traverses through different compartments of the cell through its lifetime. This review describes the experiments addressing the interaction of ANP with the NPRA, the receptor-mediated internalization and stoichiometric distribution of ANP-NPRA complexes from cell surface to cell interior, and its release into culture media. It is hypothesized that after internalization, the ligand-receptor complexes dissociate inside the cell and a population of NPRA recycles back to plasma membrane. Subsequently, some of the dissociated ligand molecules escape the lysosomal degradative pathway and are released intact into culture media, which reenter the cell by retroendocytotic mechanisms. By utilizing the pharmacologic and physiologic perturbants, the emphasis has been placed on the cellular regulation and processing of ligand-receptor complexes in intact cells. I conclude the discussion by examining the data available on the utilization of deletion mutations of NPRA cDNA, which has afforded experimental insights into the mechanisms the cell utilizes in modulating the expression and functioning of NPRA.Key words: atrial natriuretic peptide receptor-A, guanylyl cyclase receptors, ANP-binding, internalization and recycling of receptor, lysosomal hydrolysis.

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