AT₂ receptor activation induces natriuresis and lowers blood pressure.
AT₂ receptor activation induces natriuresis and lowers blood pressure.
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DOI：
10.1161/circresaha.115.304110
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发表时间：
2014-07-18
影响因子：
20.1
通讯作者：
Carey RM
中科院分区：
文献类型：
--
作者：
Kemp BA;Howell NL;Gildea JJ;Keller SR;Padia SH;Carey RM
化合物21(C-21)是一种高度选择性的非肽AT2受体激动剂。[目的]验证肾近端小管血管紧张素Ⅱ受体(AT2Rs)诱导大鼠和小鼠钠尿和降压的假说。静脉注射血管紧张素Ⅱ受体拮抗剂PD-123319(PD)可使大鼠尿钠(Na+)排泄量增加10倍(P<；0.0001)，这种排钠作用可被肾间质(RI)直接注射血管紧张素Ⅱ受体拮抗剂PD-21所阻断。C-21增加了Na+(FeNa；P<；0.05)和Li(Feli；P<；0.01)的排泄分数，而不改变肾脏血流动力学功能。AT2R的激活增加了肾近端小管细胞顶膜AT2R蛋白(P<；0.001)，但不改变AT2R的总表达和内化/灭活的Na+-H+交换器-3(NHE-3)和Na+/K+-ATPase(NKA)。C-21诱导的钠尿伴随着RI环化GMP(cGMP；P<；0.01)的增加，C-21诱导的UNaV和RI cGMP增加可被RI一氧化氮合酶(NO)抑制剂L-NAME或缓激肽(BK)B2受体拮抗剂icatibant所阻断。在血管紧张素II(Ang II)灌流的实验性高血压模型中，用C-21激活肾脏AT2R可阻止Na+滞留并降低血压。AT2R的激活启动其向RPTC顶膜的移位，NHE-3和NKA的内化以BK-NO-cGMP依赖的方式诱导钠尿。在Ang II依赖型高血压患者，肾内AT2R激活可防止Na+滞留并降低血压。AT2R激活有望成为治疗液体滞留状态和高血压的RPT利钠/利尿靶点。
Compound 21 (C-21) is a highly selective non-peptide AT2 receptor (AT2R) agonist. To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure (BP) in Sprague-Dawley rats and mice. In rats, AT2R activation with intravenous C-21 increased urinary sodium (Na+) excretion (UNaV) by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial (RI) infusion of specific AT2R antagonist PD-123319 (PD). C-21 increased fractional excretion of Na+ (FENa; P<0.05) and lithium (FELi; P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell (RPTC) apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na+- H+ exchanger-3 (NHE-3) and Na+/K+ATPase (NKA). C-21-induced natriuresis was accompanied by an increase in RI cyclic GMP (cGMP; P<0.01); C-21-induced increases in UNaV and RI cGMP were abolished by RI nitric oxide (NO) synthase inhibitor L-NAME or bradykinin (BK) B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na+ retention and lowered BP in the angiotensin II (Ang II) infusion model of experimental hypertension. AT2R activation initiates its translocation to the RPTC apical membrane and the internalization of NHE-3 and NKA inducing natriuresis in a BK-NO-cGMP-dependent manner. Intrarenal AT2R activation prevents Na+ retention and lowers BP in Ang II-dependent hypertension. AT2R activation holds promise as a RPT natriuretic/diuretic target for the treatment of fluid retaining states and hypertension.