In vivo regulation of AT1a receptor-mediated intracellular uptake of [125I]Val5-ANG II in the kidneys and adrenals of AT1a receptor-deficient mice

Abstract

Using type 1a angiotensin receptor (AT_1a) receptor-deficient (Agtr1a−/−) mice and in vivo autoradiography, we tested the hypothesis that intracellular uptake of ANG II in the kidney and adrenal glands is primarily mediated by AT_1a receptors and that the response is regulated by prevailing endogenous ANG II. After pretreatment of wild-type (Agtr1a+/+) and Agtr1a−/− mice ( n = 6–9 each group) with or without captopril (25 mg·kg⁻¹·day⁻¹) or losartan (10 mg·kg⁻¹·day⁻¹) for 2 wk, [¹²⁵I]Val⁵-ANG II was infused for 60 min. Intracellular uptake of [¹²⁵I]Val⁵-ANG II was determined by quantitative in vivo autoradiography after washout of circulating [¹²⁵I]Val⁵-ANG II. Basal intracellular ANG II levels were 65% lower in the kidney ( P < 0.001), but plasma ANG II levels were threefold higher, in Agtr1a−/− than wild-type mice ( P < 0.01). Although plasma [¹²⁵I]Val⁵-ANG II levels were similar, urinary excretion of [¹²⁵I]Val⁵-ANG II was fourfold higher in Agtr1a−/− mice ( P < 0.001). By contrast, intracellular [¹²⁵I]Val⁵-ANG II levels were ∼80% lower in the kidney and adrenal glands of Agtr1a−/− mice ( P < 0.01). Captopril decreased endogenous plasma and renal ANG II levels ( P < 0.01) but increased intracellular uptake of [¹²⁵I]Val⁵-ANG II in the kidney and adrenal glands of wild-type and Agtr1a−/− mice ( P < 0.01). Losartan largely blocked renal and adrenal uptake of [¹²⁵I]Val⁵-ANG II in wild-type and Agtr1a−/− mice. Thus 80% of intracellular ANG II uptake in the kidney and adrenal glands is mediated by AT_1a receptors, whereas AT_1b receptor- and other non-receptor-mediated mechanisms account for 20% of the response. Our results suggest that AT_1a receptor-mediated uptake of extracellular ANG II may play a physiological role in the kidney and adrenal glands.