Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Background Strain C57BL/6J Donor Strain 129P2 via E14TG2a ES cell line   Donating Investigator Oliver Smithies,   University of North Carolina

Appearance
black
Related Genotype: a/a

Description
Homozygotes are viable and fertile. Homozygotes show elevated blood pressure on both high and low salt diets. Heterozygous mice show normal blood pressure on a low salt diet but elevated blood pressue on a high salt diet.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Nppa^tm1Unc/Nppa⁺

        involves: 129P2/OlaHsd * C57BL/6J

• cardiovascular system phenotype
• abnormal heart right ventricle pressure
  • after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in right ventricular (RV) pressure are significantly higher in heterozygous than in wild-type mice (63±7% vs. 45±10%, respectively)   (MGI Ref ID J:64898)
• heart right ventricle hypertrophy
  • after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in heterozygous than in wild-type (29±4% vs. 26±5%, respectively)   (MGI Ref ID J:64898)
• salt-sensitive hypertension
  • when fed on standard chow (0.8% NaCl) for 2 weeks, heterozygotes display normal blood pressures and normal heart rates relative to wild-type   (MGI Ref ID J:76312)
  • when fed on high salt chow (8% NaCl) for 2 weeks, heterozygotes become hypertensive, with blood pressures elevated by 27 mm Hg relative to wild-type; heart rates remain unaffected relative to wild-type   (MGI Ref ID J:76312)

Nppa^tm1Unc/Nppa^tm1Unc

        involves: 129P2/OlaHsd * C57BL/6

• cardiovascular system phenotype
• *normal* cardiovascular system phenotype
  • homozygotes show no differences in body weight or hematocrit relative to wild-type mice under both normoxic and chronically hypoxic conditions   (MGI Ref ID J:54986)
• • abnormal cardiovascular system physiology
    • autonomic ganglion blockade induces comparable per cent reductions in CO, HR, and stroke volume in both genotypes; however, in mutants, the concomitant decrease in ABP (%) is significantly higher than in wild-type mice and is accompanied by a significant reduction in total peripheral resistance   (MGI Ref ID J:53877)
  • • abnormal systemic arterial blood pressure
      • intracerebroventricular ANP or losartan results in significant (and rapid) hypotension only in homozygous mutant mice   (MGI Ref ID J:63072)
      • notably, mutant and wild-type mice show comparable reductions in mean ABP after intravenous injection of vasopressin V1-receptor antagonist, suggesting that increased central AT1-receptor activation, but not systemic vasopressin, sustains chronic hypertension in mutant mice   (MGI Ref ID J:63072)
    • • hypertension
        • homozygotes exhibit significant increases in blood pressures (8 to 23 mm Hg) when they are fed standard (0.5% NaCl) and intermediate (2% NaCl) salt diets for 2-3 weeks   (MGI Ref ID J:76312)
        • the heart rates of homozygotes are comparable to those of wild-type and heterozygous littermates   (MGI Ref ID J:76312)
      • • salt-sensitive hypertension
          • when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit significantly increased basal arterial blood pressures (139±5 mm Hg) relative to wild-type mice (82±1 mm Hg)   (MGI Ref ID J:57623)
          • chronic treatment with the AT1 antagonist losartan has no effect on ABP in wild-type mice, but reduces ABP to wild-type levels in salt-fed mutant mice   (MGI Ref ID J:57623)
          • regardless of the state of alertness (i.e. conscious vs. anesthetized), homozygotes develop salt-sensitive hypertension (135±3 mm Hg) after prolonged maintenance (>1 wk) on a high-salt (HS; 8% NaCl) diet compared with both homozygotes (115±2 mm Hg) and wild-type (110±5 mm Hg) mice maintained on a low-salt (LS; 0.008% NaCl) diet   (MGI Ref ID J:95900)
      • increased systemic arterial diastolic blood pressure
        • homozygotes display elevated baseline arterial blood pressure (132±4 mm Hg) relative to wild-type mice (95±2 mm Hg)   (MGI Ref ID J:53877)
    • abnormal vascular resistance
      • chronically hypertensive homozygotes exhibit elevated baseline total peripheral resistance relative to normotensive wild-type mice; no differences in stroke volume are observed   (MGI Ref ID J:53877)
    • decreased cardiac output
      • homozygotes display a tendency towards reduced cardiac output (CO) values, as a result of reduced basal heart rate (HR); however, the differences in basal CO and HR do not reach statistical significance   (MGI Ref ID J:53877)
    • increased heart rate
      • when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit significantly increased basal heart rates (504± 20 beats/min) relative to wild-type (425±25 beats/min)   (MGI Ref ID J:57623)
      • chronic treatment with the AT1 antagonist losartan has no effect on HR in wild-type mice, but reduces HR to wild-type levels in salt-fed mutant mice   (MGI Ref ID J:57623)
    • increased right ventricle peak pressure
      • after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in right ventricular (RV) pressure are significantly higher in homozygous than in wild-type mice (104±17% vs. 45±10%, respectively)   (MGI Ref ID J:64898)
      • under normoxic conditions, homozygotes exhibit higher right ventricular peak pressure (RVPP) than wild-type mice   (MGI Ref ID J:54986)
      • after 3 weeks of hypoxia, homozygotes show a higher RVPP than heterozygous or wild-type mice   (MGI Ref ID J:54986)
    • pulmonary hypertension
      • homozygotes develop severe hypoxic pulmonary hypertension, as shown by significant differences in RVPP, RV/BW, RV/LV+S, or % of muscularized pulmonary vessels between hypoxia-adapted homozygotes and wild-type mice   (MGI Ref ID J:54986)
  • abnormal vascular smooth muscle morphology
    • under both normoxic and hypoxic conditions, homozygotes display a higher % of muscularized peripheral pulmonary vessels relative to heterozygous or wild-type mice   (MGI Ref ID J:54986)
    • under normoxic conditions, homozygotes exhibit a higher % of partially muscularized peripheral pulmonary vessels   (MGI Ref ID J:54986)
    • after 3 wks of hypobaric hypoxia, homozygotes exhibit a higher % of fully muscularized peripheral pulmonary vessels   (MGI Ref ID J:54986)
  • enlarged heart
    • on intermediate salt diets (2% NaCl), homozygotes exhibit cardiac enlargement relative to wild-type   (MGI Ref ID J:76312)
  • • heart left ventricle hypertrophy
      • under normoxic and chronically hypoxic conditions, homozygotes display a higher left ventricle plus septum weight-to-body weight (LV+S/BW) ratio than heterozygous and wild-type mice   (MGI Ref ID J:54986)
      • LV+S/BW is 49% and 38% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls   (MGI Ref ID J:54986)
    • heart right ventricle hypertrophy
      • under normoxic and chronically hypoxic conditions, homozygotes display a higher right ventricle weight-to-body weight (RV/BW) ratio than heterozygous and wild-type mice   (MGI Ref ID J:54986)
      • RV/BW is 60% and 53% greater in normoxic and chronically hypoxic conditions, respectively, relative to wild-type controls   (MGI Ref ID J:54986)
      • the RV/LV+S ratio is higher in homozygous mutants than that in heterozygous or wild-type mice under hypoxic but not under normoxic conditions   (MGI Ref ID J:54986)
      • after a 5-wk hypoxic exposure (10% O2), hypoxia-induced increases in RV mass are significantly higher in homozygous than in wild-type (38±4% vs. 26±5%, respectively)   (MGI Ref ID J:64898)
    • increased heart weight
      • on intermediate salt diets (2% NaCl), homozygotes exhibit a greater ratio of heart weight to body weight than both heterozygous and wild-type   (MGI Ref ID J:76312)
• hematopoietic system phenotype
• decreased hematocrit
  • after 2 wk on a high-salt diet, homozygotes exhibit significantly reduced hematocrits relative to wild-type mice, suggesting relative salt-retention during chronic high-salt maintainance   (MGI Ref ID J:76312)
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype
  • homozygotes fed on a HS-diet (8% NaCl) for 4 weeks, display a comparable cumulative dietary intake of food and water and urinary excretion of fluid and electrolytes relative to wild-type; chronic treatment with losartan has no effect on these parameters   (MGI Ref ID J:57623)
• • abnormal renal sodium reabsorbtion
    • after 2 wks on 8% NaCl, homozygotes show increased sodium reabsorption relative to wild-type mice   (MGI Ref ID J:95900)
  • abnormal renin activity
    • in homozygotes maintained on a high-salt (HS; 8% NaCl) diet, the salt-sensitive hypertensive response is time-dependent (>1 wk latency), and is associated with failure to downregulate plasma renin activity (PRA)   (MGI Ref ID J:95900)
    • in contrast, wild-type mice respond to HS diet with an appropriate reduction in PRA relative to wild-type mice maintained on low-salt diet (LS; 0.008% NaCl), and remain normotensive for the duration of the dietary regimen   (MGI Ref ID J:95900)
  • increased circulating adrenaline level
    • when fed on a HS-diet (8% NaCl) for 4 weeks, homozygotes exhibit a 10-fold increase in baseline total plasma catecholamine levels (norepinephrine plus epinephrine) relative to wild-type mice, indicating an abnormally elevated sympathetic tone   (MGI Ref ID J:57623)
    • chronic treatment with the AT1 antagonist losartan reduces plasma catecholamine to approximately wild-type levels in salt-fed mutant mice   (MGI Ref ID J:57623)
    • notably, plasma aldosterone does not differ significantly between genotypes and is not altered by losartan   (MGI Ref ID J:57623)
• muscle phenotype
• abnormal vascular smooth muscle morphology
  • under both normoxic and hypoxic conditions, homozygotes display a higher % of muscularized peripheral pulmonary vessels relative to heterozygous or wild-type mice   (MGI Ref ID J:54986)
  • under normoxic conditions, homozygotes exhibit a higher % of partially muscularized peripheral pulmonary vessels   (MGI Ref ID J:54986)
  • after 3 wks of hypobaric hypoxia, homozygotes exhibit a higher % of fully muscularized peripheral pulmonary vessels   (MGI Ref ID J:54986)
• renal/urinary system phenotype
• abnormal renal sodium reabsorbtion
  • after 2 wks on 8% NaCl, homozygotes show increased sodium reabsorption relative to wild-type mice   (MGI Ref ID J:95900)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Nppa^tm1Unc related

Cardiovascular Research
Hypertension
      diet-induced

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Nppatm1Unc
Allele Name		targeted mutation 1, University of North Carolina
Allele Type		Targeted (knock-out)
Common Name(s)		ANP-; proANP-;
Mutation Made By		Oliver Smithies,   University of North Carolina
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Nppa, natriuretic peptide type A
Chromosome		4
Gene Common Name(s)		ANF; ANP; ATFB6; Anf; CDD-ANF; PND; Pnd; RATANF; atrial natriuretic peptide; natriuretic peptide precursor A;
General Note		Phenotypic Similarity to Human Syndrome: Salt-Sensitive Hypertension (J:76312).
Molecular Note		11 bp of exon 2 was replaced with a neomycin resistance gene via homologous recombination. Radioimmunoassay of plasma and atria from homozygous mutant animals did not detect protein product. [MGI Ref ID J:76312]

Genotyping

Genotyping Information

Genotyping Protocols

Nppa^tm1Unc, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

John SW; Krege JH; Oliver PM; Hagaman JR; Hodgin JB; Pang SC; Flynn TG; Smithies O. 1995. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267(5198):679-81. [PubMed: 7839143]  [MGI Ref ID J:76312]

Additional References

Sun JZ; Chen SJ; Majid-Hasan E; Oparil S; Chen YF. 2002. Dietary salt supplementation selectively downregulates NPR-C receptor expression in kidney independently of ANP. Am J Physiol Renal Physiol 282(2):F220-7. [PubMed: 11788435]  [MGI Ref ID J:75607]

Nppa^tm1Unc related

Ackermann U; Azizi N. 2000. Increased central AT(1)-receptor activation, not systemic vasopressin, sustains hypertension in ANP knockout mice. Am J Physiol Regul Integr Comp Physiol 278(6):R1441-5. [PubMed: 10848509]  [MGI Ref ID J:63072]

Feng JA; Perry G; Mori T; Hayashi T; Oparil S; Chen YF. 2003. Pressure-independent enhancement of cardiac hypertrophy in atrial natriuretic peptide-deficient mice. Clin Exp Pharmacol Physiol 30(5-6):343-9. [PubMed: 12859424]  [MGI Ref ID J:103080]

Franco V; Chen YF; Oparil S; Feng JA; Wang D; Hage F; Perry G. 2004. Atrial natriuretic peptide dose-dependently inhibits pressure overload-induced cardiac remodeling. Hypertension 44(5):746-50. [PubMed: 15452027]  [MGI Ref ID J:103584]

Honrath U; Chong CK; Melo LG; Sonnenberg H. 1999. Effect of saline infusion on kidney and collecting duct function in atrial natriuretic peptide (ANP) gene 'knockout' mice. Can J Physiol Pharmacol 77(6):454-7. [PubMed: 10537232]  [MGI Ref ID J:57410]

Houng AK; McNamee RA; Kerner A; Sharma P; Mohamad A; Tronolone J; Reed GL. 2009. Atrial natriuretic peptide increases inflammation, infarct size, and mortality after experimental coronary occlusion. Am J Physiol Heart Circ Physiol 296(3):H655-61. [PubMed: 19122164]  [MGI Ref ID J:146553]

John SW; Veress AT; Honrath U; Chong CK; Peng L; Smithies O; Sonnenberg H. 1996. Blood pressure and fluid-electrolyte balance in mice with reduced or absent ANP. Am J Physiol 271(1 Pt 2):R109-14. [PubMed: 8760210]  [MGI Ref ID J:113046]

Klinger JR; Warburton RR; Pietras LA; Smithies O; Swift R; Hill NS. 1999. Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice. Am J Physiol 276(5 Pt 1):L868-74. [PubMed: 10330043]  [MGI Ref ID J:54986]

Li P; Wang D; Lucas J; Oparil S; Xing D; Cao X; Novak L; Renfrow MB; Chen YF. 2008. Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102(2):185-92. [PubMed: 17991884]  [MGI Ref ID J:141565]

Melo LG; Veress AT; Ackermann U; Pang SC; Flynn TG; Sonnenberg H. 1999. Chronic hypertension in ANP knockout mice: contribution of peripheral resistance. Regul Pept 79(2-3):109-15. [PubMed: 10100923]  [MGI Ref ID J:53877]

Melo LG; Veress AT; Ackermann U; Steinhelper ME; Pang SC; Tse Y; Sonnenberg H. 1999. Chronic regulation of arterial blood pressure in ANP transgenic and knockout mice: role of cardiovascular sympathetic tone. Cardiovasc Res 43(2):437-44. [PubMed: 10536674]  [MGI Ref ID J:59693]

Melo LG; Veress AT; Chong CK; Ackermann U; Sonnenberg H. 1999. Salt-sensitive hypertension in ANP knockout mice is prevented by AT1 receptor antagonist losartan. Am J Physiol 277(3 Pt 2):R624-30. [PubMed: 10484477]  [MGI Ref ID J:57623]

Melo LG; Veress AT; Chong CK; Pang SC; Flynn TG; Sonnenberg H. 1998. Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity. Am J Physiol 274(1 Pt 2):R255-61. [PubMed: 9458926]  [MGI Ref ID J:95900]

Mori T; Chen YF; Feng JA; Hayashi T; Oparil S; Perry GJ. 2004. Volume overload results in exaggerated cardiac hypertrophy in the atrial natriuretic peptide knockout mouse. Cardiovasc Res 61(4):771-9. [PubMed: 14985074]  [MGI Ref ID J:102124]

O'Tierney PF; Tse MY; Pang SC. 2007. Elevated renal norepinephrine in proANP gene-disrupted mice is associated with increased tyrosine hydroxylase expression in sympathetic ganglia. Regul Pept 143(1-3):90-6. [PubMed: 17482290]  [MGI Ref ID J:136761]

Sangaralingham SJ; Tse MY; Pang SC. 2007. Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice. J Endocrinol 194(1):143-152. [PubMed: 17592028]  [MGI Ref ID J:122390]

Sun JZ; Chen SJ; Li G; Chen YF. 2000. Hypoxia reduces atrial natriuretic peptide clearance receptor gene expression in ANP knockout mice. Am J Physiol Lung Cell Mol Physiol 279(3):L511-9. [PubMed: 10956626]  [MGI Ref ID J:64898]

Sun JZ; Chen SJ; Majid-Hasan E; Oparil S; Chen YF. 2002. Dietary salt supplementation selectively downregulates NPR-C receptor expression in kidney independently of ANP. Am J Physiol Renal Physiol 282(2):F220-7. [PubMed: 11788435]  [MGI Ref ID J:75607]

Vera N; Tse MY; Watson JD; Sarda S; Steinhelper ME; John SW; Flynn TG; Pang SC. 2000. Altered expression of natriuretic peptide receptors in proANP gene disrupted mice. Cardiovasc Res 46(3):595-603. [PubMed: 10912470]  [MGI Ref ID J:84437]

Wang D; Oparil S; Feng JA; Li P; Perry G; Chen LB; Dai M; John SW; Chen YF. 2003. Effects of pressure overload on extracellular matrix expression in the heart of the atrial natriuretic peptide-null mouse. Hypertension 42(1):88-95. [PubMed: 12756220]  [MGI Ref ID J:102952]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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