ANGIOTENSIN-II TYPE 1A RECEPTOR-DEFICIENT MICE WITH HYPOTENSION AND HYPERRENINEMIA

Angiotensin (AT) II, the bioactive octapeptide in the renin-angiotensi n system that plays a key role in cardiovascular homeostasis, exerts i ts multiple effects through the different types of AT receptors, AT1a, AT1b, and AT2. Previously, we showed chronic hypotension in angiotens inogen (the precursor of AT)-deficient mice and a dramatic increase in renin mRNA levels in its kidney, but it remains unclear which types o f AT receptors regulate the blood pressure and renin gene expression, In order to elucidate the physiological roles of AT1a receptor, we gen erated mutant mice with a targeted replace ment of the AT1a receptor l oci by the lacZ gene, In the heterozygous mutant mice, the strong lacZ staining was found in the glomerulus and juxtaglomerular apparatus of the renal cortex, which coincided with that of the signals detected b y in situ hybridization, Chronic hypotension was observed in the heter ozygous and homozygous mutant mice, with 10 and 22 mm Mg lower systoli c blood pressure, respectively, than that of wild-type littermates. Bo th the levels of renin mRNA in the kidney and plasma renin activity we re markedly increased only in the homozygous mutant mice, These result s demonstrated that an AT1a-mediated signal transduction pathway is, a t least in part, involved in the regulation of blood pressure and reni n gene expression.