Renal angiotensin II type-2 receptors are upregulated and mediate the candesartan-induced natriuresis/diuresis in obese Zucker rats
Renal angiotensin II type-2 receptors are upregulated and mediate the candesartan-induced natriuresis/diuresis in obese Zucker rats
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DOI：
10.1161/01.hyp.0000151622.47814.6f
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发表时间：
2005-02-01
期刊：
影响因子：
8.3
通讯作者：
Hussain, T
中科院分区：
文献类型：
--
作者：
Hakam, AC;Hussain, T
近年来，血管紧张素Ⅱ 2型（AT（2））受体在病理状态下肾/心血管功能中的作用受到越来越多的关注。本研究旨在确定AT（2）受体在利钠/利尿中的功能作用，并比较肥胖和瘦Zucker大鼠（12周龄）肾小管AT（2）受体表达水平。在麻醉下，坎地沙坦（血管紧张素II 1型[AT（1）]特异性拮抗剂; 100 μ g/kg推注）在肥胖大鼠中产生的尿钠排泄/利尿作用比在瘦大鼠中更大。给予坎地沙坦后，特异性AT（2）拮抗剂PD 123319（50 μ g/kg/min）可消除坎地沙坦对肥胖大鼠的利钠/利尿作用，但对瘦大鼠无效。输注AT（2）受体激动剂CGP-42112 A（1 μ g/kg/min），肥胖大鼠的钠和尿排泄量比瘦大鼠的增加更大。使用特异性抗体和抗原阻断肽通过Western印迹法证实刷状缘和基底外侧膜中存在AT 2受体表达。对条带的光密度分析显示，肥胖大鼠的两种膜中AT（2）受体蛋白的含量比瘦大鼠增加了约1.5至2.0倍。我们的研究结果表明，AT（2）受体的上调，在介导AT（1）受体阻滞剂在肥胖Zucker大鼠中的利钠/利尿作用中发挥作用。我们推测AT（2）受体通过促进钠排泄，可能保护肥胖Zucker大鼠对抗与钠和水潴留相关的血压升高。
Recently, there has been a growing interest in studying the role of angiotensin II type-2 (AT(2)) receptor in renal/cardiovascular function in pathological conditions. The present study was designed to determine the functional role of the AT(2) receptors on natriuresis/diuresis and compare the level of the tubular AT(2) receptor expression in obese and lean Zucker rats ( 12 weeks old). Under anesthesia, candesartan ( angiotensin II type 1 [AT(1)]-specific antagonist; 100 mug/kg bolus) produced natriuresis/diuresis to a greater degree in obese than in lean rats. The specific AT(2) antagonist PD123319 (50 mug/kg per minute) after candesartan administration abolished the natriuretic/diuretic effects of candesartan in obese rats but not in lean rats. Infusion of AT(2) receptor agonist, CGP-42112A ( 1 mug/kg per minute), produced greater increase in sodium and urine excretion over basal in obese than in lean rats. The presence of the AT2 receptor expression in the brush-border and basolateral membranes was confirmed by Western blotting using specific antibody and antigen-blocking peptide. Densitometric analysis of the bands revealed approximate to 1.5- to 2.0-fold increase in the AT(2) receptor proteins in both membranes of obese compared with lean rats. Our results suggest upregulation of the AT(2) receptors, which play a role in mediating the natriuretic/diuretic effects of AT(1) receptor blockers in obese Zucker rats. We speculate that AT(2) receptors, by promoting sodium excretion, may protect obese Zucker rats against blood pressure increase associated with sodium and water retention.