VASCULAR DAMAGE WITHOUT HYPERTENSION IN TRANSGENIC RATS EXPRESSING PRORENIN EXCLUSIVELY IN THE LIVER

We have developed a transgenic animal model to investigate the effects of overexpression of rat prorenin on the cardiovascular system. Two t ransgenic rat lines were generated in which rat prorenin expression wa s directed to the liver by a human al-antitrypsin promoter. Liver-spec ific expression was confirmed by RNase protection assay. Plasma proren in concentrations in transgenic rats were increased 400-fold in the ma les of both lines but were increased only two- to threefold in the fem ales, Thus, transgene expression exhibited sexual dimorphism, Blood pr essures were not significantly higher in transgenic rats than in nontr ansgenic controls. The ratio of heart weight to body weight was greate r in male transgenic rats than in the nontransgenic controls, Histolog ical analysis revealed severe renal lesions and hypertrophic cardiomyo cytes in transgenic males only. This transgenic model demonstrates a l ikely role of prorenin in the development of cardiac and renal patholo gy independent of hypertension. These animals will facilitate studies of the effects of blockade of the renin-angiotensin system and other p harmacological interventions on the development and treatment of cardi ac, vascular, and renal lesions induced by changes in this system in t he absence of chronic hypertension.