Genetic deletion of AT1areceptors attenuates intracellular accumulation of ANG II in the kidney of AT1areceptor-deficient mice

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Abstract
We and others have previously shown that high levels of ANG II are accumulated in the rat kidney via a type 1 (AT1) receptor-mediated mechanism, but it is not known which AT1receptor is involved in this process in rodents. We tested the hypothesis that AT1areceptor-deficient mice (Agtr1a−/−) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT1areceptor-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 AT1antagonist losartan (10 mg·kg−1·day−1po) 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 AT1breceptors ( 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 ∼20% ( P < 0.05). These results demonstrate a predominant role of AT1areceptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT1breceptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT1areceptors.