Description

Strain Information

Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator David Garbers,   U.T. Southwestern Medical Center

Description
Mice that are homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA) was detected. Homozygous mutant mice have elevated systolic, diastolic and mean blood pressure when compared to wildtype. Heterozygous mutant mice display systolic, diastolic and mean blood pressure that are slightly elevated above wildtype levels. Blood pressure in mutant mice remains elevated independent of salt content in diet. Infusion treatment of atrial natriuretic peptide in mutant mice does not result in the increased urine output or sodium excretion response seen in wildtype mice. Plasma volume expansion to release natriuretic/diuretic factors from the heart fails to induce increased urine output, sodium excretion and cyclic GMP excretion in the mutant. The same plasma volume expansion in wildtype mice results in a 12-fold increase in urine output, a 6-fold increase in sodium excretion and a 4-fold increase in cyclic GMP excretion in the urine. Mutant mice excrete only 30% of the normal level of urinary cyclic GMP. The Donating Investigator reports this mutant strain also exhibits cardiac hypertrophy and cardiac fibrosis. The phenotype of this mutant strain, salt insensitive hypertension, resembles that of half of all human patients with essential hypertension. This mutant mouse strain represents a model that may be useful in studies related to essential hypertension.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 4 of the targeted gene. The construct was electroporated into 129S7/SvEvBrd-Hprt⁺ derived AB-1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts.

Control Information

	Control
	002448 129S1/SvImJ
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Npr1^tm1Gar/Npr1⁺

        involves: 129S7/SvEvBrd * C57BL/6J

• cardiovascular system phenotype
• increased blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), heterozygotes exhibit a 7.7 mm Hg increase in mean blood pressure relative to wild-type mice; no significant changes in heart rates are observed
• increased diastolic blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), heterozygotes exhibit a 5.9 mm Hg increase in diastolic blood pressure relative to wild-type mice
• increased systolic blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), heterozygotes exhibit a 10.5 mm Hg increase in systolic blood pressure relative to wild-type mice
• salt-resistant hypertension (MGI Ref ID J:30007)
  • heterozygotes display salt-resistant hypertension: on a low (0.008% NaCl), normal (0.7% NaCl) and high (8% NaCl) salt diet, their blood pressures and heart rates remain unchanged
  • a high (8% NaCl) salt diet fails to change hematocrit or body weight, suggesting the possibility of increased natriuresis; no differences in aldosterone and atrial natriuretic peptide concentrations are observed

Npr1^tm1Gar/Npr1^tm1Gar

        involves: 129S7/SvEvBrd * C57BL/6J

• lethality-prenatal/perinatal
• *normal* lethality-prenatal/perinatal (MGI Ref ID J:30007)
  • at 3 weeks, homozygotes are slightly (but significantly) underrepresented, at least partly due to the presence of hydrops fetalis in 10% of mutant embryos; however, stage of lethality is not speficied
  • no histological abnormalities are detected in heart, vasculature or kidneys at less than 5 months of age
• cardiovascular system phenotype
• abnormal blood pressure (MGI Ref ID J:42893)
  • in wild-type mice, ANP evoked a significant reduction in BP at 500 ng/kg/min, a rate which resulted in a plasma concentration of 0.8 nM; in contrast, ANP failed to lower BP in mutant mice even at infusion rates of 50 µg/kg/min
  • CNP evoked a significant reduction in BP at much higher infusion rates (50 µg/kg/min), resulting in a plasma concentration of 18.3 nM, with no significant differences between wild-type and mutant mice
• increased blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), homozygotes exhibit a 19.7 mm Hg increase in mean blood pressure relative to wild-type mice; no significant changes in heart rates are observed
• increased diastolic blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), homozygotes exhibit a 15.3 mm Hg increase in diastolic blood pressure relative to wild-type mice
• increased systolic blood pressure (MGI Ref ID J:30007)
  • on a standard rodent chow (0.7% NaCl), homozygotes exhibit a 27.4 mm Hg increase in systolic blood pressure relative to wild-type mice
• salt-resistant hypertension (MGI Ref ID J:30007)
  • homozygotes display salt-resistant hypertension: on a low (0.008% NaCl), normal (0.7% NaCl) and high (8% NaCl) salt diet, their blood pressures and heart rates remain unchanged
  • a high (8% NaCl) salt diet fails to change hematocrit or body weight, suggesting the possibility of increased natriuresis; no differences in aldosterone and atrial natriuretic peptide concentrations are observed
• abnormal vasodilation (MGI Ref ID J:42893)
  • atrial natriuretic peptide (ANP) or B-type natriuretic peptide (BNP) half-maximally relaxed KCl-precontracted aortic rings in wild-type mice at ~24 nM, but failed to relax aortas in mutant mice, even at micromolar concentrations
  • in contrast, C-type natriuretic peptide (CNP) caused half-maximal relaxation at 335 and 146 nM in aortas from either wild-type or null mice, respectively (no significant difference)
• homeostasis/metabolism phenotype
• hydrops fetalis (MGI Ref ID J:30007)
  • ~10% of homozygotes exhibit hydrops fetalis
• increased circulating atrial natriuretic factor (MGI Ref ID J:42893)
  • homozygous mutant mice exhibit increased basal concentrations of ANP relative to wild-type mice (~279 ± 109 pM vs ~159 ± 111 pM, respectively)
  • in contrast, basal concentrations of circulating CNP are below the detectable limit in both wild-type and mutant mice

Npr1^tm1Gar/Npr1^tm1Gar

        B6.129-Npr1^tm1Gar

• cardiovascular system phenotype
• decreased infarction size (MGI Ref ID J:70496)
  • at 2 days after myocardial ischemia/reperfusion, homozygotes exhibit a 20% reduction in myocardial infarct size relative to wild-type mice
  • reduced infarct size is associated with concomitant reductions in PMN infiltration, coronary endothelial cell expression of P-selectin, and activation of NF-kappaB
• immune system phenotype
• impaired neutrophil migration (MGI Ref ID J:70496)
  • in response to myocardial ischemia/reperfusion, homozygotes exhibit a significant reduction in the number of PMNs infiltrating the myocardium relative to wild-type mice
  • reduced PMN emigration is corroborated by reduced cardiac MPO activity in infarct areas of mutant mice
• homeostasis/metabolism phenotype
• decreased infarction size (MGI Ref ID J:70496)
  • at 2 days after myocardial ischemia/reperfusion, homozygotes exhibit a 20% reduction in myocardial infarct size relative to wild-type mice
  • reduced infarct size is associated with concomitant reductions in PMN infiltration, coronary endothelial cell expression of P-selectin, and activation of NF-kappaB

View Research Applications

Research Applications

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

Npr1^tm1Gar related

Cardiovascular Research
Heart Abnormalities
Hypertension

Genes & Alleles

Gene & Allele Information

Allele Symbol		Npr1tm1Gar
Allele Name		targeted mutation 1, David L Garbers
Allele Type		Targeted (knock-out)
Common Name(s)		GC-A KO; GC-A-;
Mutation Made By		David Garbers,   U.T. Southwestern Medical Center
Strain of Origin		129S7/SvEvBrd-Hprt1<+>
ES Cell Line Name		AB1
ES Cell Line Strain		129S7/SvEvBrd-Hprt1<+>
Gene Symbol and Name		Npr1, natriuretic peptide receptor 1
Chromosome		3
Gene Common Name(s)		AI893888; ANPRA; ANPa; GC-A; GUC2A; GUCY2A; Gca; NPR-A; NPRA; Pndr; expressed sequence AI893888; guanylyl cyclase-A;
Molecular Note		Insertion of a neomycin resistance cassette into exon 4, which encodes part of the extra-cellular putative ligand-binding domain, disrupted the gene. Stable, wild-type size transcript was not detected in liver or kidney from homozygous mutant mice. [MGI Ref ID J:30007]

Genotyping

Genotyping Information

Genotyping Protocols

NEOTD (Generic Neo), STD PCR, vers. 1
Npr1^tm1Gar, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Lopez MJ; Wong SK; Kishimoto I; Dubois S; Mach V; Friesen J; Garbers DL; Beuve A. 1995. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378(6552):65-8. [PubMed: 7477288]  [MGI Ref ID J:30007]

Additional References

Npr1^tm1Gar related

Chusho H; Ogawa Y; Tamura N; Suda M; Yasoda A; Miyazawa T; Kishimoto I; Komatsu Y; Itoh H; Tanaka K; Saito Y; Garbers DL; Nakao K. 2000. Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways. Endocrinology 141(10):3807-13. [PubMed: 11014237]  [MGI Ref ID J:108806]

Dubois SK; Kishimoto I; Lillis TO; Garbers DL. 2000. A genetic model defines the importance of the atrial natriuretic peptide receptor (guanylyl cyclase-A) in the regulation of kidney function. Proc Natl Acad Sci U S A 97(8):4369-73. [PubMed: 10760303]  [MGI Ref ID J:126140]

Hunt LM; Hogeland EW; Henry MK; Swoap SJ. 2004. Hypotension and bradycardia during caloric restriction in mice are independent of salt balance and do not require ANP receptor. Am J Physiol Heart Circ Physiol 287(4):H1446-51. [PubMed: 15191892]  [MGI Ref ID J:95588]

Izumi T; Saito Y; Kishimoto I; Harada M; Kuwahara K; Hamanaka I; Takahashi N; Kawakami R; Li Y; Takemura G; Fujiwara H; Garbers DL; Mochizuki S; Nakao K. 2001. Blockade of the natriuretic peptide receptor guanylyl cyclase-A inhibits NF-kappaB activation and alleviates myocardial ischemia/reperfusion injury. J Clin Invest 108(2):203-13. [PubMed: 11457873]  [MGI Ref ID J:70496]

Kilic A; Velic A; De Windt LJ; Fabritz L; Voss M; Mitko D; Zwiener M; Baba HA; van Eickels M; Schlatter E; Kuhn M. 2005. Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation 112(15):2307-17. [PubMed: 16216978]  [MGI Ref ID J:116814]

Kirchhof P; Fabritz L; Kilic A; Begrow F; Breithardt G; Kuhn M. 2004. Ventricular arrhythmias, increased cardiac calmodulin kinase II expression, and altered repolarization kinetics in ANP receptor deficient mice. J Mol Cell Cardiol 36(5):691-700. [PubMed: 15135664]  [MGI Ref ID J:102133]

Kong X; Wang X; Xu W; Behera S; Hellermann G; Kumar A; Lockey RF; Mohapatra S; Mohapatra SS. 2008. Natriuretic peptide receptor a as a novel anticancer target. Cancer Res 68(1):249-56. [PubMed: 18172317]  [MGI Ref ID J:131033]

Li Y; Kishimoto I; Saito Y; Harada M; Kuwahara K; Izumi T; Hamanaka I; Takahashi N; Kawakami R; Tanimoto K; Nakagawa Y; Nakanishi M; Adachi Y; Garbers DL; Fukamizu A; Nakao K. 2004. Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. Endocrinology 145(2):951-8. [PubMed: 14592959]  [MGI Ref ID J:88703]

Li Y; Kishimoto I; Saito Y; Harada M; Kuwahara K; Izumi T; Takahashi N; Kawakami R; Tanimoto K; Nakagawa Y; Nakanishi M; Adachi Y; Garbers DL; Fukamizu A; Nakao K. 2002. Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart. Circulation 106(13):1722-8. [PubMed: 12270869]  [MGI Ref ID J:103221]

Lopez MJ; Garbers DL; Kuhn M. 1997. The guanylyl cyclase-deficient mouse defines differential pathways of natriuretic peptide signaling. J Biol Chem 272(37):23064-8. [PubMed: 9287305]  [MGI Ref ID J:42893]

Nakanishi M; Saito Y; Kishimoto I; Harada M; Kuwahara K; Takahashi N; Kawakami R; Nakagawa Y; Tanimoto K; Yasuno S; Usami S; Li Y; Adachi Y; Fukamizu A; Garbers DL; Nakao K. 2005. Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice. Hypertension 46(2):441-7. [PubMed: 15998711]  [MGI Ref ID J:114365]

Steinmetz M; Potthast R; Sabrane K; Kuhn M. 2004. Diverging vasorelaxing effects of C-type natriuretic peptide in renal resistance arteries and aortas of GC-A-deficient mice. Regul Pept 119(1-2):31-7. [PubMed: 15093694]  [MGI Ref ID J:102436]

Tokudome T; Horio T; Kishimoto I; Soeki T; Mori K; Kawano Y; Kohno M; Garbers DL; Nakao K; Kangawa K. 2005. Calcineurin-nuclear factor of activated T cells pathway-dependent cardiac remodeling in mice deficient in guanylyl cyclase A, a receptor for atrial and brain natriuretic peptides. Circulation 111(23):3095-104. [PubMed: 15939815]  [MGI Ref ID J:112245]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a 129S7 background and is maintained on the 129S6/SvEvTac background as a heterozygote.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	002448 129S1/SvImJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

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.

---

Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.