ANP-mediated inhibition of distal nephron fractional sodium reabsorption in wild-type and mice overexpressing natriuretic peptide receptor

Atrial natriuretic peptide (ANP) elicits natriuresis; however, the relative contributions of proximal and distal nephron segments to the overall ANP-induced natriuresis have remained uncertain. This study was performed to characterize the effects of ANP on distal nephron sodium reabsorption determined after blockade of the two major distal nephron sodium transporters with amiloride (5 μg/g body wt) plus bendroflumethiazide (12 μg/g body wt) in male anesthetized C57/BL6 and natriuretic peptide receptor-A gene (Npr1) targeted four-copy mice. The lower dose of ANP (0.1 ng·g body wt−1·min−1, n = 6) increased distal sodium delivery (DSD, 2.4 ± 0.4 vs. 1.6 ± 0.2 μeq/min, P < 0.05) but did not change fractional reabsorption of DSD compared with control (86.3 ± 2.0 vs. 83.9 ± 3.6%, P > 0.05), thus limiting the magnitude of the natriuresis. In contrast, the higher dose (0.2 ng·g body wt−1·min−1, n = 6) increased DSD (2.8 ± 0.3 μeq/min, P < 0.01) and also decreased fractional reabsorption of DSD (67.4 ± 4.5%, P < 0.01), which markedly augmented the natriuresis. In Npr1 gene-duplicated four-copy mice ( n = 6), the lower dose of ANP increased urinary sodium excretion (0.6 ± 0.1 vs. 0.3 ± 0.1 μeq/min, P < 0.05) and decreased fractional reabsorption of DSD compared with control (72.2 ± 3.4%, P < 0.05) at similar mean arterial pressures (91 ± 6 vs. 92 ± 3 mmHg, P > 0.05). These results provide in vivo evidence that ANP-mediated increases in DSD alone exert modest effects on sodium excretion and that inhibition of fractional reabsorption of distal sodium delivery is requisite for the augmented natriuresis in response to the higher dose of ANP or in Npr1 gene-duplicated mice.

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In Vitro And In Vivo Bronchodilator Profile Of PL-3994, A Novel Cyclic Peptide (Hept-Cyclo(Cys-His-Phe-D-Ala-Gly-Arg-D-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg Mimetic]-NH2) Natriuretic Peptide Receptor-A (NPR-A) Agonist That Is Resistant To Neutral Endopeptidase (NEP)

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a2831 ◽

2012 ◽

Author(s):

Douglas W. Hay ◽

Xiaomei Chen ◽

Marie Makhlina ◽

Trevor J. Hallam ◽

Jeffrey D. Edelson

Keyword(s):

Natriuretic Peptide ◽

Cyclic Peptide ◽

Neutral Endopeptidase ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00185.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. L714-L723 ◽

Cited By ~ 15

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.

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In vitro and in vivo pharmacological profile of PL-3994, a novel cyclic peptide (Hept-cyclo(Cys-His-Phe-d-Ala-Gly-Arg-d-Nle-Asp-Arg-Ile-Ser-Cys)-Tyr-[Arg mimetic]-NH2) natriuretic peptide receptor-A agonist that is resistant to neutral endopeptidase and acts as a bronchodilator

Pulmonary Pharmacology & Therapeutics ◽

10.1016/j.pupt.2012.11.001 ◽

2013 ◽

Vol 26 (2) ◽

pp. 229-238 ◽

Cited By ~ 15

Author(s):

Jeffrey D. Edelson ◽

Marie Makhlina ◽

Kevin R. Silvester ◽

Shailesh S. Vengurlekar ◽

Xiaomei Chen ◽

...

Keyword(s):

Natriuretic Peptide ◽

Cyclic Peptide ◽

Neutral Endopeptidase ◽

Natriuretic Peptide Receptor ◽

Pharmacological Profile ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A

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Natriuretic peptide receptor a promotes gastric malignancy through angiogenesis process

Cell Death and Disease ◽

10.1038/s41419-021-04266-7 ◽

2021 ◽

Vol 12 (11) ◽

Author(s):

Zheng Li ◽

Hao Fan ◽

Jiacheng Cao ◽

Guangli Sun ◽

Sen Wang ◽

...

Keyword(s):

Gastric Cancer ◽

Natriuretic Peptide ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Angiogenesis Process ◽

Natriuretic Peptide Receptor A ◽

Vitro Analysis ◽

In Vitro Analysis

AbstractGastric cancer (GC) ranks the third among global cancer-related mortality, especially in East Asia. Angiogenesis plays an important role in promoting tumor progression, and clinical trials have demonstrated that anti-angiogenesis therapy is effective in GC management. Natriuretic peptide receptor A (NPRA) functions significantly in promoting GC development and progression. Whether NPRA can promote angiogenesis of GC remains unclear. Tumor samples collection and immunohistochemical experiment showed that the expression of NPRA was positively correlated with the expression of CD31 and vessel density. In vivo and in vitro analysis showed that NPRA could promote GC-associated angiogenesis and tumor metastasis. Results of Co-IP/MS showed that NPRA could prevent HIF-1α from being degraded by binding to HIF-1α. Protection of HIF-1α improved VEGF levels and thus promoted angiogenesis. In summary, NPRA protected HIF-1α from proteolysis by binding to HIF-1α, increased the expression of HIF-1α, and promoted GC angiogenesis. This study has discovered a new mechanism for NPRA to promote gastric cancer development and a new regulatory mechanism for HIF-1α.

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Discovery and in vivo effects of novel human natriuretic peptide receptor A (NPR-A) agonists with improved activity for rat NPR-A

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2017.11.006 ◽

2017 ◽

Vol 25 (24) ◽

pp. 6680-6694 ◽

Cited By ~ 1

Author(s):

Takehiko Iwaki ◽

Taisaku Tanaka ◽

Kazuo Miyazaki ◽

Yamato Suzuki ◽

Yoshihiko Okamura ◽

...

Keyword(s):

Natriuretic Peptide ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A ◽

In Vivo Effects

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Regulation of natriuretic peptide receptor-A gene expression and stimulation of its guanylate cyclase activity by transcription factor Ets-1

Bioscience Reports ◽

10.1042/bsr20080094 ◽

2009 ◽

Vol 29 (1) ◽

pp. 57-70 ◽

Cited By ~ 17

Author(s):

Prerna Kumar ◽

Gevoni Bolden ◽

Kiran K. Arise ◽

Stephen T. Krazit ◽

Kailash N. Pandey

Keyword(s):

Natriuretic Peptide ◽

Gene Transcription ◽

Guanylate Cyclase ◽

Promoter Activity ◽

Target Cells ◽

Mrna Levels ◽

Natriuretic Peptide Receptor ◽

Peptide Receptor ◽

Natriuretic Peptide Receptor A ◽

Npr1 Gene

ANP (atrial natriuretic peptide) exerts its biological effects by binding to GC (guanylate cyclase)-A/NPR (natriuretic peptide receptor)-A, which generates the second messenger cGMP. The molecular mechanism mediating Npr1 (coding for GC-A/NPRA) gene regulation and expression is not well understood. The objective of the present study was to elucidate the mechanism by which Ets-1 [Ets (E twenty-six) transformation-specific sequence] contributes to the regulation of Npr1 gene transcription and expression. Chromatin immunoprecipitation and gel-shift assays confirmed the in vivo and in vitro binding of Ets-1 to the Npr1 promoter. Overexpression of Ets-1 enhanced significantly Npr1 mRNA levels, protein expression, GC activity and ANP-stimulated intracellular accumulation of cGMP in transfected cells. Depletion of endogenous Ets-1 by siRNA (small interfering RNA) dramatically decreased promoter activity by 80%. Moreover, methylation of the Npr1 promoter region (−356 to +55) reduced significantly the promoter activity and hypermethylation around the Ets-1 binding sites directly reduced Ets-1 binding to the Npr1 promoter. Collectively, the present study demonstrates that Npr1 gene transcription and GC activity of the receptor are critically controlled by Ets-1 in target cells.

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

Physiological Genomics ◽

10.1152/physiolgenomics.00079.2007 ◽

2007 ◽

Vol 31 (2) ◽

pp. 193-202 ◽

Cited By ~ 17

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.

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