Complementation of reduced survival, hypotension, and renal abnormalities in angiotensinogen-deficient mice by the human renin and human angiotensinogen genes.

Abstract

The aim of this study was to determine whether elements of the human renin-angiotensin system (RAS) could function- ally 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 angio- tensinogen 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 5 139) were geno- typed at each locus and the population was stratified into two groups: the first containing both human transgenes (RA 1 ) and the second containing zero or one, but not both human transgenes (RA 2 ). Despite appropriate Mendelian ratios of RA 2 mice that were wildtype ( 1 / 1 ), heterozygous ( 1 / 2 ), and homozygous ( 2 / 2 ) for the deletion of mAgt at birth, there was reduced survival of RA 2 mAgt 2 / 2 mice to adulthood ( P , 0.001 by x 2 ). In contrast, we observed ap- propriate Mendelian ratios of RA 1 mAgt 1 / 1 , RA 1 mAgt 1 / 2 , and RA 1 mAgt 2 / 2 mice at birth and in adults ( P. 0.05 by x 2 ). These results demonstrate that the presence of both hu- man transgenes rescues the postnatal lethality in mAgt 2 / 2 mice. The renal histopathology exhibited by RA 2 mAgt 2 / 2 mice, including thickened arterial walls, severe fibrosis, lymphocytic infiltration, and atrophied parenchyma, was also rescued in the RA 1 mAgt 2 / 2 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 1 mice ( z 20 mmHg per mAgt gene copy, P , 0.001). BP in RA 1 mAgt 2 / 2 mice (132 6 3, n 5 14) was intermediate between wild-type (RA 2 mAgt 1 / 1 , 105 6 2, n 5 9) and RA 1 mAgt 1 / 1 (174 6 3, n 5 10) mice. These studies establish that the human renin and angio- tensinogen genes can functionally replace the mouse angio- tensinogen gene, and provides proof in principle that we can examine the regulation of elements of the human RAS and