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(Circulation Research. 1995;77:73-79.)
© 1995 American Heart Association, Inc.

Articles

Regulation of Aldosterone Biosynthesis by Adrenal Renin Is Mediated Through AT₁ Receptors in Renin Transgenic Rats

Massimo Volpe, Speranza Rubattu, Bruna Gigante, Detlev Ganten, Antonio Porcellini, Rosaria Russo, Michele Romano, Iolanda Enea, Min Ae Lee, Bruno Trimarco

From the Departments of Internal Medicine (M.V., S.R., B.G., R.R., M.R., I.E., B.T.) and Cellular and Molecular Pathology (A.P.), School of Medicine, Federico II University, Napoli, Italy; Max-Delbrück Centrum (D.G.), Berlin-Buch, Germany; and the Cardiovascular Division, Department of Cardiology, Children's Hospital, Harvard Medical School, Boston, Mass (S.R., M.L.).

Correspondence to Massimo Volpe, MD, Department of Internal Medicine, Federico II University, Via Sergio Pansini, 5, 80131 Naples, Italy.

Abstract The transgenic (TG) rat (mREN2)27 is characterized by overexpression of the additional mouse Ren-2^d gene in the adrenal cortex with marked suppression of renal renin. We have previously shown that in salt-depleted TG rats enhanced activation of mineralocorticoid biosynthesis is associated with selective stimulation of adrenal renin. To investigate whether the local renin-angiotensin system regulates aldosterone biosynthesis in the adrenal cortex of TG rats, we studied the effects of the AT₁–angiotensin subtype receptor antagonist DuP 753 on aldosterone production in 5-week-old TG rats during salt restriction. All the rats (n=56) were shifted from regular chow to a diet containing only 0.04% NaCl for 1 week. The AT₁-receptor antagonist DuP 753 (10 mg/kg per day in drinking water) was administered to 27 of these rats during low-salt diet. Subgroups of rats were killed at 0, 4, and 7 days. Low-salt diet increased both adrenal renin activity (from 31±3 to 77±4 and 85±2 ng angiotensin I · h^-1 · mg protein^-1 at 4 and 7 days, respectively; P<.001) and mRNA (by 68.4±10% and 80±17% from baseline, P<.05). In addition, salt restriction was associated with increases of AT₁-receptor subtype mRNA, aldosterone-synthase cytochrome P450 mRNA (by 130±56% and 227±33% at 4 and 7 days, respectively; P<.05), and plasma aldosterone (from 184±33 to 402±79 and 338±59 pg/mL, P<.05), whereas renal renin activity did not change, renin mRNA levels remained almost undetectable, and plasma renin activity showed a transient increase. In contrast, in TG rats treated with DuP 753 salt restriction was associated with increases of renal renin mRNA and renal and plasma renin activity, whereas the stimulation of aldosterone-synthase mRNA was markedly attenuated, and plasma aldosterone did not change. Separate analysis of mouse transgene and endogenous rat renin performed by RNase protection assay in 18 additional TG rats and in 18 age- and sex-matched Sprague-Dawley rats showed that the mouse transgene was prominently expressed in the adrenal glands of TG rats in all experimental conditions. In conclusion, our data show that AT₁-receptor antagonism abolishes the adrenal renin–related stimulation of the aldosterone biosynthesis produced by salt restriction in TG rats. This indicates that in this model the adrenal renin-angiotensin system regulates the mineralocorticoid production via the AT₁-receptor subtype.

Key Words: aldosterone • angiotensin • losartan • renin • transgenic rats

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