RGD Reference Report - GENETIC MUTATION OF RECOMBINATION ACTIVATING GENE 1 IN DAHL SALT-SENSITIVE RATS ATTENUATES HYPERTENSION AND RENAL DAMAGE. - Rat Genome Database

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GENETIC MUTATION OF RECOMBINATION ACTIVATING GENE 1 IN DAHL SALT-SENSITIVE RATS ATTENUATES HYPERTENSION AND RENAL DAMAGE.

Authors: Mattson, DL  Lund, H  Guo, C  Rudemiller, N  Geurts, AM  Jacob, HJ 
Citation: Mattson DL, etal., Am J Physiol Regul Integr Comp Physiol. 2013 Jan 30.
RGD ID: 7207429
Pubmed: PMID:23364523   (View Abstract at PubMed)
PMCID: PMC3602820   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpregu.00304.2012   (Journal Full-text)

Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672-706 of recombination activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13 base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1 null mutant rats have a significant reduction in T- and B-lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1 null rats fed a 4.0% NaCl diet for three weeks. The infiltration of T-cells into the kidney following high salt was significantly blunted in the Rag1 null rats (1.7+/-0.6 x 10(5) cells/kidney) compared to the Dahl SS (5.6+/-0.9 x 10(5) cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rat were significantly lower in Rag1 null mutants (158+/-3 mmHg and 60+/-16 mg/day, respectively) than in SS rats (180+/-11 mmHg and 251+/-37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed high salt was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.



Disease Annotations    
Albuminuria  (IMP,ISO)
hypertension  (IMP,ISO)
Hypertensive Nephropathy  (IMP,ISO)

Phenotype Annotations    

Mammalian Phenotype

Objects Annotated

Genes (Rattus norvegicus)
Rag1  (recombination activating 1)
Rag1em1Mcwi  (recombination activating gene 1; zinc finger nuclease induced mutant 1, Medical College of Wisconsin)
Rag1em2Mcwi  (recombination activating gene 1; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Rag1  (recombination activating 1)

Genes (Homo sapiens)
RAG1  (recombination activating 1)

Strains
SS-Rag1em1Mcwi-/-  (SS-Rag1em1Mcwi-/Rag1em1Mcwi-)
SS-Rag1em1Mcwi  (NA)
SS-Rag1em2Mcwi-/-  (SS-Rag1em2Mcwi-/Rag1em2Mcwi-)
SS-Rag1em2Mcwi  (NA)


Additional Information