Reduced growth, abnormal kidney structure, and type 2 (AT(2)) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT(1A) andAT(1B) receptors for angiotensin II

The classically recognized functions of the renin-angiotensin system are me diated by type 1 (AT(1)) angiotensin receptors. Whereas man possesses a sin gle AT(1) receptor, there are two AT(1) receptor isoforms in rodents (AT(1A ) and AT(1B)) that are products of separate genes (Agtr1a and Agtr1b), We h ave generated mice lacking AT(1B) (Agtr1b -/-) and both AT(1A) and AT(1B) r eceptors (Agtr1a -/- Agtr1b -/-). Agtr1b -/- mice are healthy without an ab normal phenotype. In contrast, Agtr1a -/- Agtr1b -/- mice have diminished g rowth, vascular thickening within the kidney, and atrophy of the inner rena l medulla, This phenotype is virtually identical to that seen in angiotensi nogen-deficient (Agt -/-) and angiotensin-converting enzyme-deficient (Ace -/-) mice that are unable to synthesize angiotensin IT. Agtr1a -/- Agtr1b - /- mice have no systemic presser response to infusions of angiotensin II, b ut they respond normally to another vasoconstrictor, epinephrine. Blood pre ssure is reduced substantially in the Agtr1a -/- Agtr1b -/- mice and follow ing administration of an angiotensin converting enzyme inhibitor, their blo od pressure increases paradoxically, We suggest that this is a result of in terruption of AT(2)-receptor signaling. In summary, our studies suggest tha t both AT(1) receptors promote somatic growth and maintenance of normal kid ney structure, The absence of either of the AT(1) receptor isoforms alone c an be compensated in varying degrees by the other isoform, These studies re affirm and extend the importance of AT(1) receptors to mediate physiologica l functions of the renin-angiotensin system.