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1 Hypertension and Vascular Division, Henry Ford Hospital, Detroit, Michigan, United States
2 Department of Physiology, SL39, Tulane University School of Medicine, New Orleans,, Louisiana, United States
3 Hypertension and Vascular Division, Henry Ford Hospital, Detroit, Michigan, United States; Department of Physiology, Wayne State University School of Medicine, 5374 Scott Hall, Detroit, Michigan, 48202, United States
* To whom correspondence should be addressed. E-mail: jzhuo1{at}hfhs.org.
We and others have shown that angiotensin II (Ang II) is accumulated in the rat kidney via an AT1 receptor-mediated mechanism, but it is not known which AT1 receptor mediates this response. We tested the hypothesis that AT1a receptor-deficient mice (Agtr1a-/-) are unable to take up Ang II intracellularly in the kidney due to the absence of AT1a receptor-mediated endocytosis. Wild-type (Agtr1a+/+), heterozygous (Agtr1a+/-) and Agtr1a-/- were treated with vehicle, Ang II (40 ng/min, i.p.), or Ang II plus losartan (10 mg/kg/day, p.o.) for 2 weeks. In wild-type mice, Ang II induced hypertension, increased kidney weight, caused pressure natriuresis, and elevated plasma and whole kidney Ang II levels (p<0.01). These responses to Ang II were attenuated by losartan. Agtr1a-/- mice had lower basal systolic pressure, smaller kidneys with fewer AT1b receptors , higher basal 24 hour urinary sodium excretion, 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, 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 overall blood pressure and renal regulation in response to Ang II, but also suggest that AT1b receptors may play a limited role when AT1a receptors are deleted.
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