FUNCTIONAL EXPRESSION OF THE HUMAN ANGIOTENSINOGEN GENE IN TRANSGENICMICE

The renin-angiotensin system is a major determinant of arterial pressu re and volume homeostasis in mammals through the actions of angiotensi n II, the proteolytic digestion product of angiotensinogen. Molecular genetic studies in several human populations have revealed genetic lin kage between the angiotensinogen gene and both hypertension and increa sed plasma angiotensinogen. Transgenic mice were generated with a huma n angiotensinogen genomic clone to develop an animal model to examine tissue- and cell-specific expression of the gene and to determine if o verexpression of angiotensinogen results in hypertension. Human angiot ensinogen mRNA was expressed in transgenic mouse liver, kidney, heart, adrenal gland, ovary, brain, and white and brown adipose tissue and, in kidney, was exclusively localized to epithelial cells of the proxim al convoluted tubules, Plasma levels of human angiotensinogen were app roximately 150-fold higher in transgenic mice than that found normally in human plasma. The blood pressure of mice bearing the human angiote nsinogen gene was normal but infusion of a single bolus dose of purifi ed human renin resulted in a transient increase in blood pressure of a pproximately 30 mm Hg within 2 min. These results suggest that abnorma lities in the angiotensinogen gene resulting in increased circulating levels of angiotensinogen could potentially contribute in part to the pathogenesis of essential hypertension.