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AT₁ receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats

¹Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan; ²St. Vincent's Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria; and ³Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan

Submitted 25 May 2005 ; accepted in final form 14 December 2005

Angiotensin IV (ANG IV), an active ANG II fragment, has been shown to induce systemic and renal cortical effects by binding to ANG IV (AT₄) receptors and activating unique signaling transductions unrelated to classical type 1 (AT₁) or type 2 (AT₂) receptors. We tested whether ANG IV exerts systemic and renal cortical effects on blood pressure, renal microvascular smooth muscle cells (VSMCs), and glomerular mesangial cells (MC) and, if so, whether AT₁ receptor-activated signaling is involved. In anesthetized rats, systemic infusion of ANG II, ANG III, or ANG IV (0.01, 0.1, and 1.0 nmol·kg^–1·min^–1 iv) caused dose-dependent increases in mean arterial pressure (MAP) and decreases in renal cortical blood flow (CBF; P < 0.01). ANG II also induced dose-dependent reductions in renal medullary blood flow (P < 0.01), whereas ANG IV did not. ANG IV-induced pressor and renal cortical vasoconstriction were completely abolished by AT₁ receptor blockade with losartan (5 mg/kg iv; P < 0.05). When ANG IV (1 nmol·kg^–1·min^–1) was infused directly in the renal artery, CBF was reduced by >30%, and the response was also blocked by losartan (P < 0.01). In the renal cortex, unlabeled ANG IV displaced ¹²⁵I-labeled [Sar¹,Ile⁸]ANG II binding, whereas unlabeled ANG II (10 µM) inhibited ¹²⁵I-labeled Nle¹-ANG IV (AT₄) binding in a concentration-dependent manner (P < 0.01). In freshly isolated renal VSMCs, ANG IV (100 nM) increased intracellular Ca²⁺ concentration, and the effect was blocked by losartan and U-73122, a selective inhibitor of phospholipase C/inositol trisphosphate/Ca²⁺ signaling (1 µM). In cultured rat MCs, ANG IV (10 nM) induced mitogen-activated protein kinase extracellular/signal-regulated kinase 1/2 phosphorylation via AT₁ receptor- and phospholipase C-activated signaling. These results suggest that, at nanomolar concentrations, ANG IV can increase MAP and induce renal cortical effects by interacting with AT₁ receptor-activated signaling.

angiotensin II; angiotensin IV; angiotensin type 1 receptor; angiotensin type 4 receptor; renal cortical blood flow; mitogen-activated protein kinases

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