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1Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit; 3Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan; and 2Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana
Submitted 12 December 2006 ; accepted in final form 25 May 2007
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 AT1 receptor is involved in this process in rodents. We tested the hypothesis that AT1a receptor-deficient mice (Agtr1a–/–) are unable to accumulate ANG II intracellularly in the kidney because of the absence of AT1a 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 AT1 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 AT1b 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 
20% (P < 0.05). These results demonstrate a predominant role of AT1a receptors in blood pressure regulation and in the renal responses to long-term ANG II administration, that AT1b receptors may play a limited role in blood pressure control and mediating intrarenal ANG II accumulation in the absence of AT1a receptors.
kidney; losartan; receptor endocytosis; urinary sodium excretion
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