Faculty Collaboration Database

Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes. J Clin Invest 1997 Mar 15;99(6):1258-64

Date

03/15/1997

Pubmed ID

9077534

Pubmed Central ID

PMC507940

DOI

10.1172/JCI119283

Scopus ID

2-s2.0-0030952323 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

The aim of this study was to determine whether elements of the human renin-angiotensin system (RAS) could functionally replace elements of the mouse RAS by complementing the reduced survival and renal abnormalities observed in mice carrying a gene-targeted deletion of the mouse angiotensinogen gene (mAgt). Double transgenic mice containing the human renin (HREN) and human angiotensinogen (HAGT) genes were bred to mice heterozygous for the mAgt deletion and the compound heterozygotes were identified and intercrossed. The resulting progeny (n = 139) were genotyped at each locus and the population was stratified into two groups: the first containing both human transgenes (RA+) and the second containing zero or one, but not both human transgenes (RA-). Despite appropriate Mendelian ratios of RA- mice that were wildtype (+/+), heterozygous (+/-), and homozygous (-/-) for the deletion of mAgt at birth, there was reduced survival of RA- mAgt-/- mice to adulthood (P < 0.001 by chi2). In contrast, we observed appropriate Mendelian ratios of RA+ mAgt+/+, RA+ mAgt+/-, and RA+ mAgt-/- mice at birth and in adults (P > 0.05 by chi2). These results demonstrate that the presence of both human transgenes rescues the postnatal lethality in mAgt-/- mice. The renal histopathology exhibited by RA- mAgt-/- mice, including thickened arterial walls, severe fibrosis, lymphocytic infiltration, and atrophied parenchyma, was also rescued in the RA+ mAgt-/- mice. Direct arterial blood pressure recordings in conscious freely moving mice revealed that BP (in mmHg) varied proportionally to mAgt gene copy number in RA+ mice (approximately 20 mmHg per mAgt gene copy, P < 0.001). BP in RA+ mAgt-/- mice (132+/-3, n = 14) was intermediate between wild-type (RA- mAgt+/+, 105+/-2, n = 9) and RA+ mAgt+/+ (174+/-3, n = 10) mice. These studies establish that the human renin and angiotensinogen genes can functionally replace the mouse angiotensinogen gene, and provides proof in principle that we can examine the regulation of elements of the human RAS and test the significance of human RAS gene variants by a combined transgenic and gene targeting approach.

Author List

Davisson RL, Kim HS, Krege JH, Lager DJ, Smithies O, Sigmund CD

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensinogen
Animals
Breeding
Female
Genes, Lethal
Genetic Complementation Test
Genotype
Humans
Hypotension
Kidney Diseases
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pedigree
Phenotype
Renin
Transgenes