Overview

Also Known As:eNOS^-/- C57BLKS/J ^db

eNOS^- C57BLKS/J Lepr^db double mutant mice harbor both the spontaneous Lepr^db mutation and nitric oxide synthase 3, endothelial cell (Nos3 or eNOS) knock-out targeted mutation. Double homozygous eNOS^-/- C57BLKS/J db/db mice (also called eNOS^-/- db/db, or db/db/eNOS-/- double mutant mice) are a robust model of type II diabetic nephropathy and may be useful for studying eNOS-mediated events in the development and progression of diabetic nephropathy.

Donating Investigator

Dr. Raymond C. Harris, Vanderbilt University Med Center

Genetic overview

Genetic Background	Generation
	N11F6+F9 (2019-12-27 00:00:00)

Nos3^tm1Unc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Nos3	nitric oxide synthase 3, endothelial cell

Lepr^db

Allele Type	Gene Symbol	Gene Name
Spontaneous	Lepr	leptin receptor

View Genetics

Research Applications

Diabetes and Obesity Research
Internal/Organ Research
Cardiovascular Research
Reproductive Biology Research
Mouse/Human Gene Homologs
Endocrine Deficiency Research
Immunology, Inflammation and Autoimmunity Research
Metabolism Research

View All Research Applications

Base Price

Starting at:

$278.00 Domestic price for female 4-week

556.00 Domestic price for breeder pair

View Price List

Details

Detailed Description

These double mutant mice harbor both the Lepr^db spontaneous mutation and the Nos3 (eNOS) targeted mutation and are congenic on C57BLKS/J genetic background. Mice homozygous for both mutations (called eNOS^-/- C57BLKS/J db/db, eNOS^-/- db/db, or db/db/eNOS-/- double mutant mice) are viable with development of type II diabetes and diabetic nephropathy. The eNOS^-/- C57BLKS/J db/db mice develop type II diabetes with significant obesity and hypertension: while both mutations are associated with insulin resistance, the mutated leptin receptor in db/db mice chiefly accounts for the observed hyperglycemia and defective leptin signaling (leading to persistent hyperphagia and obesity), and the eNOS-deficiency accounts for the moderate systemic hypertension. In addition, eNOS^-/- C57BLKS/J db/db mice exhibit rapid onset and progression of pathologic diabetic nephropathy (DN) features by 26 weeks of age; developing severe albuminuria and other DN characteristics (including arteriolar hyalinosis, increased glomerular basement membrane thickness, mesangial expansion, mesangiolysis, and focal segmental and early nodular glomerulosclerosis), also with remarkably decreased glomerular filtration rate (GFR; on the basis of impaired inulin clearance and increased serum creatinine). Double homozygous eNOS^-/- C57BLKS/J db/db mice are a robust model of type II diabetic nephropathy and may be useful for studying eNOS-mediated events in the development and progression of diabetic nephropathy.

Development

These eNOS^- C57BLKS/J Lepr^db double mutant mice were generated in the laboratory of Dr. Raymond C. Harris (Vanderbilt University) by backcrossing eNOS-mutant mice (Stock No. 002684) to C57BLKS/J inbred mice (Stock No. 000662) for ten generations, and then the resulting mice were bred with the BKS.Cg-Dock7^m +/+ Lepr^db/J repulsion stock (Stock No. 000642). Mice homozygous for the eNOS knock-out allele, heterozygous for Lepr^db, and segregating for misty (m) were sent to The Jackson Laboratory. Upon arrival, mice were bred with C57BLKS/J inbred mice (Stock No. 000662) to establish this colony (and remove misty).

The diabetes allele (Lepr^db) is a spontaneous mutation of the leptin receptor locus on chromosome 4. The eNOS knock-out targeted mutation allele (Nos3^tm1Unc) has a neomycin cassette replacing 129 bp of exon 12 of the nitric oxide synthase 3, endothelial cell locus on chromosome 5.

In 2018, A 48 SNP (single nucleotide polymorphism) panel analysis, with 43 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. One of the 43 markers, on Chromosome 11, was segregating.

Control Suggestions

BKS.129P2(Cg)-Nos3^tm1Unc/J mice (Stock No. 018295) may be an appropriate control.
000662 C57BLKS/J

Additional Information

Considerations for Choosing Controls

Selected References

Zhao HJ; Wang S; Cheng H; Zhang MZ; Takahashi T; Fogo AB; Breyer MD; Harris RC. 2006. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17(10):2664-9PubMed: 16971655 MGI: J:135864

View All References

Genetics

Nos3^tm1Unc

Allele Symbol: Nos3^tm1Unc

Allele Name	targeted mutation 1, University of North Carolina
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	ecNOS-; eNOS-; eNOSKO; NOS3-
Gene Symbol and Name	Nos3, nitric oxide synthase 3, endothelial cell
Gene Synonym(s)
Strain of Origin	129P2/OlaHsd
Chromosome	5
Molecular Note	A 1.2 kb neomycin cassette replaced 129 bp of exon 12 of the gene. This disrupted the calmodulin binding site of the protein and introduced a premature stop codon into the transcripts. Immunohistochemisty of heart and kidney sections from homozygous mutant mice confirmed that no detectable encoded protein was present.
Mutations Made By	Dr. Oliver Smithies, University of North Carolina at Chapel Hill

Lepr^db

Allele Symbol: Lepr^db

Allele Name	diabetes
Allele Type	Spontaneous
Allele Synonym(s)	db; db/db; Lep^db; Lepr-; Lepr^db-1J; leprdb
Gene Symbol and Name	Lepr, leptin receptor
Gene Synonym(s)
Strain of Origin	C57BLKS/J
Chromosome	4
General Note	Phenotypic Similarity to Human Syndrome: Gestational Diabetes J:219658
Molecular Note	An intronic G-to-T transversion in this allele created a donor splice site that causes abnormal splicing and the inclusion of 106 nt of intronic sequence in the transcript, leading to premature termination of the long cellular domain of the Ob-Rb splice form and loss of its signal transducing function.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

type 2 diabetes mellitus

Research Areas By Phenotype

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

Genotype: Nos3^tm1Unc related

Diabetes and Obesity Research
- Insulin Resistance
Internal/Organ Research
- Heart Abnormalities
Cardiovascular Research
- Heart Abnormalities
  - bradycardia
- Hypertension

Genotype: Lepr^db related

Internal/Organ Research
- Adipose Defects
Reproductive Biology Research
- Fertility Defects
Mouse/Human Gene Homologs
- obesity, morbid, with hypogonadism (rare)
Diabetes and Obesity Research
- Obesity With Diabetes
- Impaired Wound Healing
- Hyperinsulinemia
- Insulin Resistance
Endocrine Deficiency Research
- Adipose Defects
- Hypothalamus/Pituitary Defects
- Pancreas Defects
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency Associated with Other Defects
Metabolism Research

Endocrine Deficiency Research
- Adipose Defects
- Hypothalamus/Pituitary Defects
Internal/Organ Research
- Adipose Defects
- Kidney Defects
Cardiovascular Research
- Other
  - altered fat metabolism
  - altered lipoprotein profile
- Hypertension
- Metabolic Syndrome
Metabolism Research
- Lipid Metabolism
Diabetes and Obesity Research
- Obesity With Diabetes
  - severe
- Type 2 Diabetes (NIDDM)
- Hyperinsulinemia
- Insulin Resistance
  - more severe
- Hyperglycemia
Research Tools
- Diabetes and Obesity Research
Mouse/Human Gene Homologs
- diabetes mellitus, insulin-resistant

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: Lepr^db/Lepr^db Nos3^tm1Unc/Nos3^tm1Unc
BKS.Cg-Lepr Nos3

cardiovascular system phenotype

abnormal kidney afferent arteriole morphology
- arteriolar hyalinosis

increased systemic arterial systolic blood pressure
- hypertension is observed between 24-28 weeks of age, but is not significantly higher than homozygous Nos3^tm1Unc controls

growth/size/body region phenotype

increased body weight
- at 26 weeks, body weight is double that of lean and Nos3^tm1Unc controls

homeostasis/metabolism phenotype

albuminuria
- albumin/creatinine ratio (ACR) is significantly higher than all controls

hyperglycemia
- hyperglycemia is first observed between 6-8 weeks of age, but is not higher than homozygous Lepr^db control

increased circulating creatinine level
- at 26 weeks, serum creatinine is significantly higher than all controls

renal/urinary system phenotype

abnormal kidney afferent arteriole morphology
- arteriolar hyalinosis

abnormal nephron morphology

abnormal renal glomerulus morphology
- glomerular injury is significantly increased by 24-26 weeks in comparison to all controls

albuminuria
- albumin/creatinine ratio (ACR) is significantly higher than all controls

decreased renal glomerular filtration rate
- GFR is decreased in comparison to homozygous Nos3^tm1Unc and Lepr^db controls

expanded mesangial matrix
- marked mesangial expansion is observed at 26 weeks of age

glomerulosclerosis
- focal nodular sclerosis is observed at 26 weeks of age

increased renal glomerulus basement membrane thickness
- glomerular basement membrane is markedly thickened by 16 weeks in comparison to all controls

mesangiolysis
- marked mesangiolysis is observed at 26 weeks of age

renal glomerulus fibrosis
- substantial fibronectin accumulation is observed in glomeruli

References

Zhao HJ; Wang S; Cheng H; Zhang MZ; Takahashi T; Fogo AB; Breyer MD; Harris RC. 2006. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol 17(10):2664-9PubMed: 16971655 MGI: J:135864

Additional - Lepr^db related

Additional - Nos3^tm1Unc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Restriction Enzyme Digest:Lepr
- Pyrosequencing:Lepr
- End Point Analysis:Lepr
- QPCR:Generic Neo Quantitative PCR-QPCR- 1.2
- Standard PCR:Nos3
- Standard PCR:Nos3
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, mice heterozygous for the Lepr^db spontaneous mutation and homozygous for the Nos3 (eNOS^-/-) targeted mutation may be bred together. NOTE: These mice have significant breeding difficulties. Approximately 16% of Het Hom x Het Hom matings are non-productive; approximately 23% of females only produce one litter; pre-wean loss is approximately 10%; 20% of breeders are found dead prior to retirement at 6-8 months of age.
- Additional Breeding and Husbandry Support
Mating System
- See "Breeding Considerations"
Citation
When using the eNOS^-/- C57BLKS/J ^db mouse strain in a publication, please cite the originating article(s) and include JAX stock #008340 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

AX12 (Maximum)

Pricing & Availability

Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Breeder Pair

Sex

Genotype

Price

Female
Male

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Lepr<db>and Heterozygous for Nos3<tm1Unc>

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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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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General Terms and Conditions

Questions about Terms of Use

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Licensing Information

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Also Known As:eNOS-/- C57BLKS/J db

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Nos3tm1Unc

Allele Symbol: Nos3tm1Unc

Leprdb

Allele Symbol: Leprdb

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Genotype: Nos3tm1Unc related

Genotype: Leprdb related

Mammalian Phenotype Terms by Genotype

Genotype: Leprdb/Leprdb Nos3tm1Unc/Nos3tm1UncBKS.Cg-Lepr Nos3

cardiovascular system phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

renal/urinary system phenotype

References

Additional - Leprdb related

Additional - Nos3tm1Unc related

Genotyping Protocols

Breeding Considerations

Mating System

Citation

Animal Health Reports

Live Mouse

Breeder Pair

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:eNOS^-/- C57BLKS/J ^db

Nos3^tm1Unc

Allele Symbol: Nos3^tm1Unc

Lepr^db

Allele Symbol: Lepr^db

Genotype: Nos3^tm1Unc related

Genotype: Lepr^db related

Genotype: Lepr^db/Lepr^db Nos3^tm1Unc/Nos3^tm1Unc
BKS.Cg-Lepr Nos3

Additional - Lepr^db related

Additional - Nos3^tm1Unc related