Oxygen and Steroids Affect the Regulatory Role of Natriuretic Peptide Receptor-C on Surfactant Secretion by Type II Cells

2021 ◽  
Author(s):  
Rita M. Ryan ◽  
Manjeet K Paintlia ◽  
Danforth A. Newton ◽  
Demetri D Spyropoulos ◽  
Matthew W. Kemp ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Lung Epithelial Cells ◽  
Late Gestation ◽  
Mouse Lung ◽  
Type Ii Cells ◽  
Natriuretic Peptide Receptor ◽  
Type Ii ◽  
Fetal Sheep ◽  
Peptide Receptor ◽  
Surfactant Secretion

Atrial natriuretic peptide (ANP) and its receptors Natriuretic peptide receptor (NPR)-A and NRP-C are all highly expressed in alveolar epithelial type II cells (AEC2s) in the late gestation ovine fetal lung and are dramatically decreased postnatally. However, of all the components, NPR-C stimulation inhibits ANP-mediated surfactant secretion. Since alveolar oxygen increases dramatically after birth, and steroids are administered to mothers antenatally to enhance surfactant lung maturity, we investigated the effects of O2 concentration and steroids on NPR-C-mediated surfactant secretion in AEC2s. NPR-C expression was highest at 5% O2, while being suppressed by 21% O2, in cultured mouse lung epithelial cells (MLE-15s) and/or human primary AEC2s. Surfactant protein-B (SP-B) was significantly elevated in media from both in vitro and ex-vivo culture at 13% O2 versus 21% O2 in the presence of ANP or terbutaline (TER). Both ANP and C-ANP (an NPR-C agonist) attenuated TER-induced SP-B secretion; this effect was reversed by dexamethasone (DEX) pretreatment in AEC2s and by transfection with NPR-C siRNA in MLE-15 cells. DEX markedly reduced AEC2 NPR-C expression, and pregnant ewes treated with betamethasone showed reduced ANP in fetal sheep lung fluid. These data suggest that elevated O2 downregulates AEC2 NPR-C, and that steroid-mediated NPR-C downregulation in neonatal lungs may provide a novel mechanism for their effect on perinatal surfactant production.

Surfactant lipid synthesis and lamellar body formation in glycogen-laden type II cells

2004 ◽  
Vol 287 (4) ◽  
pp. L743-L751 ◽  
Author(s):  
Ross Ridsdale ◽  
Martin Post
Keyword(s):  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Lamellar Body ◽  
Late Gestation ◽  
Mouse Lung ◽  
Immunogold Electron Microscopy ◽  
Type Ii Cells ◽  
Type Ii ◽  
Energy Filtering ◽  
Glycogen Stores

Pulmonary surfactant is a lipoprotein complex that functions to reduce surface tension at the air liquid interface in the alveolus of the mature lung. In late gestation glycogen-laden type II cells shift their metabolic program toward the synthesis of surfactant, of which phosphatidylcholine (PC) is by far the most abundant lipid. To investigate the cellular site of surfactant PC synthesis in these cells we determined the subcellular localization of two key enzymes for PC biosynthesis, fatty acid synthase (FAS) and CTP:phosphocholine cytidylyltransferase-α (CCT-α), and compared their localization with that of surfactant storage organelles, the lamellar bodies (LBs), and surfactant proteins (SPs) in fetal mouse lung. Ultrastructural analysis showed that immature and mature LBs were present within the glycogen pools of fetal type II cells. Multivesicular bodies were noted only in the cytoplasm. Immunogold electron microscopy (EM) revealed that the glycogen pools were the prominent cellular sites for FAS and CCT-α. Energy-filtering EM demonstrated that CCT-α bound to phosphorus-rich (phospholipid) structures in the glycogen. SP-B and SP-C, but not SP-A, localized predominantly to the glycogen stores. Collectively, these data suggest that the glycogen stores in fetal type II cells are a cellular site for surfactant PC synthesis and LB formation/maturation consistent with the idea that the glycogen is a unique substrate for surfactant lipids.

scholarly journals C-type natriuretic peptide system in fetal ovine pulmonary vasculature

2001 ◽  
Vol 281 (2) ◽  
pp. L361-L368 ◽  
Author(s):  
Satyan Lakshminrusimha ◽  
Christopher A. D'Angelis ◽  
James A. Russell ◽  
Lori C. Nielsen ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Natriuretic Peptide ◽  
Kinase Inhibitor ◽  
Pulmonary Arteries ◽  
Late Gestation ◽  
Pulmonary Vasculature ◽  
Natriuretic Peptide Receptor ◽  
Response Curves ◽  
Peptide Receptor ◽  
Better Than

C-type natriuretic peptide (CNP) is a recently described endothelium-derived relaxing factor. CNP relaxes vascular smooth muscle and inhibits smooth muscle proliferation by binding to natriuretic peptide receptor (NPR) type B (NPR-B) and producing cGMP. Lung parenchyma and fifth-generation pulmonary arteries (PA) and veins (PV) were isolated from late-gestation fetal lambs. All three types of NPR mRNA were detected in PA and PV by RT-PCR. CNP and NPR-B immunostaining was positive in pulmonary vascular endothelium and medial smooth muscle. CNP concentration-response curves of PA and PV were compared with those of atrial natriuretic peptide (ANP) by use of standard tissue bath techniques. CNP relaxed PV significantly better than PA. ANP relaxed PA and PV equally, but ANP relaxed PA significantly better than CNP. Pretreating PA and PV with natriuretic peptide receptor blocker (HS-142-1) or cGMP-dependent protein kinase inhibitor Rp-β-phenyl-1- N 2-etheno-8-bromoguanosine 3′,5′-cyclic monophosphorothionate significantly inhibited the CNP relaxation response, indicating that the response was mediated through the NPR-cGMP pathway. We conclude that CNP is important in mediating pulmonary venous tone in the fetus.

Biallelic cGMP-dependent type II protein kinase gene (PRKG2) variants cause a novel acromesomelic dysplasia

2020 ◽  
pp. jmedgenet-2020-107177
Author(s):  
Francisca Díaz-González ◽  
Saruchi Wadhwa ◽  
Maria Rodriguez-Zabala ◽  
Somesh Kumar ◽  
Miriam Aza-Carmona ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Natriuretic Peptide ◽  
Bone Growth ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Natriuretic Peptide Receptor ◽  
Type Ii ◽  
Kinase Gene ◽  
Peptide Receptor ◽  
Dependent Type

BackgroundC-type natriuretic peptide (CNP), its endogenous receptor, natriuretic peptide receptor-B (NPR-B), as well as its downstream mediator, cyclic guanosine monophosphate (cGMP) dependent protein kinase II (cGKII), have been shown to play a pivotal role in chondrogenic differentiation and endochondral bone growth. In humans, biallelic variants in NPR2, encoding NPR-B, cause acromesomelic dysplasia, type Maroteaux, while heterozygous variants in NPR2 (natriuretic peptide receptor 2) and NPPC (natriuretic peptide precursor C), encoding CNP, cause milder phenotypes. In contrast, no variants in cGKII, encoded by the protein kinase cGMP-dependent type II gene (PRKG2), have been reported in humans to date, although its role in longitudinal growth has been clearly demonstrated in several animal models.MethodsExome sequencing was performed in two girls with severe short stature due to acromesomelic limb shortening, brachydactyly, mild to moderate platyspondyly and progressively increasing metaphyseal alterations of the long bones. Functional characterisation was undertaken for the identified variants.ResultsTwo homozygous PRKG2 variants, a nonsense and a frameshift, were identified. The mutant transcripts are exposed to nonsense-mediated decay and the truncated mutant cGKII proteins, partially or completely lacking the kinase domain, alter the downstream mitogen activation protein kinase signalling pathway by failing to phosphorylate c-Raf 1 at Ser43 and subsequently reduce ERK1/2 activation in response to fibroblast growth factor 2. They also downregulate COL10A1 and upregulate COL2A1 expression through SOX9.ConclusionIn conclusion, we have clinically and molecularly characterised a new acromesomelic dysplasia, acromesomelic dysplasia, PRKG2 type (AMDP).

Role of Natriuretic Peptide Receptor Type C in Dahl Salt-Sensitive Hypertensive Rats

Hypertension ◽  
1997 ◽  
Vol 30 (2) ◽  
pp. 177-183 ◽  
Author(s):  
Miki Nagase ◽  
Katsuyuki Ando ◽  
Takeshi Katafuchi ◽  
Akira Kato ◽  
Shigehisa Hirose ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Receptor Type ◽  
Natriuretic Peptide Receptor ◽  
Hypertensive Rats ◽  
Peptide Receptor ◽  
Type C

Allotopic antagonism of the non-peptide atrial natriuretic peptide (ANP) antagonist HS-142-1 on natriuretic peptide receptor NPR-A

2002 ◽  
Vol 362 (2) ◽  
pp. 231-237 ◽  
Author(s):  
Hugo POIRIER ◽  
Jean LABRECQUE ◽  
Julie DESCHÊNES ◽  
André DeLÉAN
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Mode Of Action ◽  
Transmembrane Domain ◽  
Peptide Binding ◽  
Natriuretic Peptide Receptor ◽  
Receptor Dimerization ◽  
Peptide Receptor ◽  
Peptide Binding Site ◽  
Atrial Natriuretic

The microbial polysaccharide HS-142-1 has been documented as an antagonist of natriuretic peptides. It inhibits activation and peptide binding to both guanylate receptors natriuretic peptide receptor (NPR)-A and NPR-B, but has no effect on the non-cyclase receptor NPR-C. At first sight the effect of HS-142-1 on peptide binding appears to be surmountable, suggesting that it might be competitive despite its chemically divergent nature. We explored its mode of action on wild-type NPR-A (WT), on a disulphide-bridged constitutively active mutant (C423S) and on truncated mutants lacking either their cytoplasmic domain (ΔKC) or both the cytoplasmic and the transmembrane domains (ECD). On the WT, HS-142-1 inhibited atrial natriuretic peptide (ANP) binding with a pK value of 6.51±0.07 (Kd = 0.31μM). It displayed a similar effect on the C423S mutant (pK = 6.31±0.11), indicating that its action might not be due to interference with receptor dimerization. HS-142-1 also inhibited ANP binding to ΔKC with a pK of 7.05±0.05 (Kd = 0.089μM), but it was inactive on ANP binding to ECD at a concentration of 10−4M, suggesting that the antagonism was not competitive at the peptide-binding site located on the ECD and that the transmembrane domain might be required. HS-142-1 also enhanced dissociation of NPR-A-bound 125I-ANP in the presence of excess unlabelled ANP, implying an allotopic (allosteric) mode of action for the antagonist.

scholarly journals Structure of the bovine atrial natriuretic peptide receptor (type C) gene

1991 ◽  
Vol 266 (17) ◽  
pp. 11122-11125
Author(s):  
T. Saheki ◽  
T. Mizuno ◽  
T. Iwata ◽  
Y. Saito ◽  
T. Nagasawa ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Receptor Type ◽  
Natriuretic Peptide Receptor ◽  
Peptide Receptor ◽  
Type C ◽  
Atrial Natriuretic Peptide Receptor ◽  
Atrial Natriuretic
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