Published Online
on September 8, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on January 27, 2003
Revised on February 24, 2003

Physiological Impact of Increased Expression of the AT₁ Angiotensin Receptor

Thu H. Le; Hyung-Suk Kim; Andrew M. Allen; Robert F. Spurney; Oliver Smithies; and Thomas M. Coffman^*

From the Department of Medicine, Duke University and Durham VA Medical Centers (T.H.L., R.F.S., T.M.C.), Durham, NC; the Department of Pathology, University of North Carolina (H.-S.K., O.S.), Chapel Hill, NC; and The Howard Florey Institute, University of Melbourne (A.M.A.), Australia.

^* To whom correspondence should be addressed. E-mail: tcoffman{at}duke.edu.

Abstract--To test the effect of increased AT₁ 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 AT₁-specific binding of ¹²⁵I-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 AT₁ receptors affect blood pressure and gene expression programs. The impact of enhanced AT₁ receptor expression on blood pressure may be blunted by systemic compensatory responses and altered signal-effector coupling in the vasculature.

Key words: hypertension, renal • renin • aldosterone • mice • gender

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