Does genetic deletion of AT1a receptors prevent intracellular accumulation of ANG II in the kidney and attenuate responses to long-term ANG II administration in mice?
The study demonstrates that AT1a receptors play a predominant role in blood pressure regulation and renal intracellular accumulation of ANG II during long-term ANG II administration.
We and others have previously shown that high levels of ANG II are accumulated in the rat kidney via a type 1 (AT(1)) receptor-mediated mechanism, but it is not known which AT(1) receptor is involved in this process in rodents. We tested the hypothesis that AT(1a) receptor-deficient mice (Agtr1a-/-) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT(1a) receptor-mediated endocytosis. Adult male wild-type (Agtr1a+/+), heterozygous (Agtr1a+/-), and Agtr1a-/- were treated with vehicle, ANG II (40 ng/min ip via osmotic minipump), or ANG II plus the AT(1) antagonist losartan (10 mg.kg(-1).day(-1) po) for 2 wk. In wild-type mice, ANG II induced hypertension (168 +/- 4 vs. 113 +/- 3 mmHg, P < 0.001), increased kidney-to-body weight ratio (P < 0.01), caused pressure natriuresis (P < 0.05), and elevated plasma and whole kidney ANG II levels (P < 0.001). Concurrent administration of ANG II with losartan attenuated these responses to ANG II. In contrast, Agtr1a-/- mice had lower basal systolic pressures (P < 0.001), smaller kidneys with much fewer AT(1b) receptors (P < 0.001), higher basal 24-h urinary sodium excretion (P < 0.01), as well as basal plasma and whole kidney ANG II levels (P < 0.01). However, intracellular ANG II levels in the kidney were lower in Agtr1a-/- mice. In Agtr1a-/- mice, ANG II slightly increased systolic pressure (P < 0.05) but had no effect on the kidney weight, urinary sodium excretion, and whole kidney ANG II levels. Losartan restored systolic pressure to basal levels and decreased whole kidney ANG II levels by approximately 20% (P < 0.05). These results demonstrate a predominant role of AT(1a) receptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT(1b) receptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT(1a) receptors.
Li et al. (2007) studied this question.