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

The classically recognized functions of the renin–angiotensin system are mediated by type 1 (AT(1)) angiotensin receptors. Whereas man possesses a single 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 have generated mice lacking AT(1B) (Agtr1b −/−) and both AT(1A) and AT(1B) receptors (Agtr1a −/−Agtr1b −/−). Agtr1b −/− mice are healthy, without an abnormal phenotype. In contrast, Agtr1a −/−Agtr1b −/− mice have diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype is virtually identical to that seen in angiotensinogen-deficient (Agt−/−) and angiotensin-converting enzyme-deficient (Ace −/−) mice that are unable to synthesize angiotensin II. Agtr1a −/−Agtr1b −/− mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine. Blood pressure is reduced substantially in the Agtr1a −/− Agtr1b −/− mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically. We suggest that this is a result of interruption of AT(2)-receptor signaling. In summary, our studies suggest that both AT(1) receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT(1) receptor isoforms alone can be compensated in varying degrees by the other isoform. These studies reaffirm and extend the importance of AT(1) receptors to mediate physiological functions of the renin–angiotensin system.