HIGH HUMAN RENIN HYPERTENSION IN TRANSGENIC RATS

We developed a model of spontaneously high human renin hypertension in the rat by producing two transgenic strains, one for human angiotensi nogen with the endogenous promoter and one for human renin with the en dogenous promoter. Neither transgenic strain was hypertensive. These s trains were then crossed, producing a double transgenic strain. The do uble transgenic rats, both males and females, developed severe hyperte nsion (mean systolic pressure, 200 mm Hg) and died after a mean of 55 days if untreated. The rats had a human plasma renin concentration of 269 +/- 381 (+/- SD) ng angiotensin I (Ang I)/mL per hour, plasma reni n activity of 177 +/- 176 ng Ang I/mL per hour, rat angiotensinogen co ncentration of 1.49 +/- 1 mu g Ang I/mL, and human angiotensinogen con centration of 78 +/- 39 mu g Ang I/mL (n = 49). Control rats had plasm a renin activity of 3.7 +/- 3.9 ng Ang I/mL per hour and rat angiotens inogen of 1.32 +/- 0.16 mu g Ang I/mL. Angiotensinogen transgene expre ssion by RNase protection assay was ubiquitously present but most prom inent in liver. Renin transgene expression was high in kidney but abse nt in liver. The rats featured severe cardiac hypertrophy, with increa sed cross section of cardiomyocytes but little myocardial fibrosis. Th e kidneys showed atrophic tubules, thickened vessel walls, and increas ed interstitium. Both the angiotensin-converting enzyme inhibitor lisi nopril and the specific human renin inhibitor remikiren lowered blood pressure to normal values. Double transgenic mice have been developed that exhibit features quite similar to those described here; their gen e expressions are similar. The specificity of rodent and human renin i s similarly documented. Although many elegant physiological studies ca n now be done in mice, rats nevertheless offer flexibility, particular ly in terms of detailed cardiac and renal physiology and pharmacology. We conclude that this double transgenic strain will facilitate simult aneous investigation of genetic and pathophysiological aspects of reni n-induced hypertension. The fact that human renin can be studied in th e rat is a unique feature of this model.