Prorenin Contributes to Angiotensin Peptide Formation in Transgenic Rats With Rat Prorenin Expression Targeted to the Liver

Abstract

We reported previously that targeted expression of rat prorenin to the liver under the control of the human alpha1-antitrypsin promoter increased plasma prorenin levels by several-hundred-fold in male transgenic rats and caused cardiac hypertrophy, severe renal lesions, and myocardial fibrosis by 20 weeks of age, despite normal blood pressure. We examined the evolution of the phenotype of male transgenic rats over 12 months and the effects of binephrectomy on the renin-angiotensin (Ang) system. Plasma prorenin levels were >1000-fold higher than in wild type littermates, whereas plasma and renal Ang II levels were no different from wild-type (WT) levels, and kidney renin levels were suppressed in transgenic rats. In contrast to our earlier report, transgenic rats had increased systolic blood pressure at 3 to 12 months of age, and only modest renal lesions and myocardial fibrosis were evident after 6 months of age. Binephrectomy reduced plasma renin activity and concentration and prorenin levels by 50% to 80% and Ang II levels by 90% in WT rats. By contrast, binephrectomy increased plasma renin activity and concentration and prorenin levels by 52.0-, 13.0-, and 5.8-fold, respectively, without change in Ang II levels in transgenic rats. We conclude that, in the animals studied in this report, elevated prorenin levels did not cause renal lesions or myocardial fibrosis during the first 6 months of age. Ang peptide formation consequent to the increased prorenin levels prevented reduction of Ang II levels after binephrectomy and was likely to have contributed to hypertension, cardiac hypertrophy, and suppression of kidney renin levels in these transgenic rats.