Physiological impact of increased expression of the AT1 angiotensin receptor

To test the effect of increased AT(1) receptor expression on blood pressure, we used gene targeting to generate mouse lines with a tandem duplication of the AT(1A) receptor gene locus (Agtr1a) along with >10 kb of 5' flanking DNA. By successive breeding, we generated mice with 3 and 4 copies of the Agtr1a gene locus on an inbred 129/Sv background. AT(1A) mRNA expression and AT(1)-specific binding of I-125-angiotensin II were increased in proportion to Agtr1a gene copy number. These animals survived in expected numbers, and their body, heart, and kidney weights were similar to wild-type, 2-copy control mice. Pressor responses to angiotensin II were blunted in the 4-copy mice compared with control mice. In male mice, there was no correlation between resting blood pressure and Agtr1a gene copy number or AT(1A) mRNA levels. However, in female mice, there was a highly significant positive correlation between blood pressure and AT(1A) receptor expression, paralleled by significant increases in aldosterone synthase expression with increase in gene copy number. Furthermore, in female but not male mice, there was a positive correlation between kallikrein and AT(1A) receptor mRNA levels and an inverse correlation between renin mRNA and Agtr1a copy number. Thus, in female but not male mice, genetic variants that increase expression of AT(1) receptors affect blood pressure and gene expression programs. The impact of enhanced AT(1) receptor expression on blood pressure may be blunted by systemic compensatory responses and altered signal-effector coupling in the vasculature.