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Physiol. Genomics 1: 3-9, 1999. First published July 15, 1999;
1094-8341/99 $5.00
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Received 20 November 1998; accepted in final form 8 March 1999.
Physiological Genomics 1:3-9 (1999)
1094-8341/99 $5.00 © 1999 American Physiological Society

Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice

ROBIN L. DAVISSON1, YUEMING DING2, DAVID E. STEC1, JAMES F. CATTERALL3 and CURT D. SIGMUND1

1 Departments of Internal Medicine and of Physiology and Biophysics
2 Genetics Program, University of Iowa College of Medicine, Iowa City, Iowa 52242
3 The Population Council, The Rockefeller University, New York, New York 10021

Davisson, Robin L., Yueming Ding, David E. Stec, James F. Catterall, and Curt D. Sigmund. Novel mechanism of hypertension revealed by cell-specific targeting of human angiotensinogen in transgenic mice. Physiol. Genomics 1: 3–9, 1999.—We tested the hypothesis that the tissue-specific intrarenal renin-angiotensin system (RAS) can participate in the regulation of blood pressure independently of its endocrine counterpart, by generating two transgenic models that differ in their tissue-specific expression of human angiotensinogen (AGT). Human AGT expression was driven by its endogenous promoter in the systemic model and by the kidney androgen-regulated protein promoter in the kidney-specific model. Using molecular, biochemical, and physiological measurements, we demonstrate that human AGT mRNA and protein are restricted to the kidney in the kidney-specific model. Plasma ANG II was elevated in the systemic model but not in the kidney-specific model. Nevertheless, blood pressure was markedly elevated in both the systemic and kidney-specific transgenic mice. Acute administration of the selective ANG II AT-1 receptor antagonist losartan lowered blood pressure in the systemic model but not in the kidney-specific model. These results provide evidence for the potential importance of the intrarenal RAS in blood pressure regulation by showing that expression of AGT specifically in the kidney leads to chronic hypertension independently of the endocrine RAS.

transgenic mice; blood pressure regulation; renal function; angiotensin II




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