AT1 receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats
AT1 receptor-activated signaling mediates angiotensin IV-induced renal cortical vasoconstriction in rats
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DOI：
10.1152/ajprenal.00221.2005
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发表时间：
2006-05-01
影响因子：
4.2
通讯作者：
Zhuo, JL
中科院分区：
文献类型：
--
作者：
Li, XC;Campbell, DJ;Zhuo, JL
血管紧张素IV(Ang IV)是Ang II的活性片段，通过与Ang IV(AT(4))受体结合并激活与经典的1型(AT(1))或2型(AT(2))受体无关的独特信号转导通路，诱导全身和肾脏的皮质效应。我们测试了Ang IV是否对血压、肾微血管平滑肌细胞(VSMCs)和肾小球系膜细胞(MC)产生全身和肾脏皮质效应，如果是，是否涉及AT(1)受体激活的信号转导。在麻醉大鼠中，全身输注血管紧张素II、血管紧张素转换酶III或血管紧张素转换酶IV(0.01、0.1和1.0nmol.Kg-(1)。静脉注射MIN(-1)后，平均动脉压(MAP)呈剂量依赖性升高，肾皮质血流量(CBF；P<；0.01)下降。血管紧张素转换酶II还引起肾髓质血流量的剂量依赖性减少(P<；0.01)，而血管紧张素转换酶IV不能。血管紧张素转换酶(AT(1))受体阻断剂氯沙坦(5 mg/kg iv；P<；0.05)可完全阻断Ang IV引起的升压和肾皮质血管收缩。当Ang IV(1nmol.Kg(-1)。Min(-1))直接注入肾动脉，脑血流量减少30%，氯沙坦也能阻断这一反应(P<；0.01)。在肾皮质，未标记的Ang IV取代了I-125标记的[Sar(1)，Ile(8)]Ang II的结合，而未标记的Ang II(10 MU M)以浓度依赖的方式抑制I-125标记的NLE(1)-Ang IV(AT(4))的结合(P<；0.01)。在新鲜分离的肾VSMC上，血管紧张素转换酶IV(100nM)可增加细胞内钙离子浓度，这种作用可被氯沙坦和磷脂酶C/肌醇三磷酸/钙离子信号选择性阻断剂U-73122(1mU/M)阻断。在培养的大鼠肾小球系膜细胞中，Ang IV(10 NM)通过AT(1)受体和磷脂酶C激活的信号通路诱导丝裂原激活的蛋白激酶胞外/信号调节激酶1/2的磷酸化。这些结果表明，在纳摩尔浓度下，Ang IV可以通过与AT(1)受体激活的信号相互作用而增加MAP并诱导肾皮质效应。
Angiotensin IV (ANG IV), an active ANG II fragment, has been shown to induce systemic and renal cortical effects by binding to ANG IV (AT(4)) receptors and activating unique signaling transductions unrelated to classical type 1 (AT(1)) or type 2 (AT(2)) 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 AT(1) 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 AT(1) 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 I-125-labeled [Sar(1), Ile(8)] ANG II binding, whereas unlabeled ANG II ( 10 mu M) inhibited I-125- labeled Nle(1)-ANG IV (AT(4)) 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 mu M). In cultured rat MCs, ANG IV ( 10 nM) induced mitogen-activated protein kinase extracellular/signal-regulated kinase 1/2 phosphorylation via AT(1) 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 AT(1) receptor-activated signaling.