Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis.
Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis.
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DOI：
10.1161/hypertensionaha.111.184788
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发表时间：
2012-02
期刊：
影响因子：
--
通讯作者：
Carey RM
中科院分区：
文献类型：
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作者：
Padia SH;Kemp BA;Howell NL;Keller SR;Gildea JJ;Carey RM
肾多巴胺 D1 样受体 (D1R) 和血管紧张素 2 型受体 (AT2R) 是重要的利尿钠受体，可平衡血管紧张素 1 型受体介导的肾小管钠 (Na+) 重吸收。在这里，我们探讨 D1R 和 AT2R 相互作用在尿钠排泄中的机制。在未肾切除的负载 Na+ 的 Sprague-Dawley 大鼠中，直接肾间质 (RI) 输注高选择性 D1R 激动剂非诺多泮 (FEN) 诱导利尿钠反应，该反应被 AT2R 特异性拮抗剂 PD-123319 (PD) 或微管聚合抑制剂诺考达唑 (NOC) 消除，但不能被肌动蛋白聚合抑制剂细胞松弛素 D 消除。免疫电镜显示，FEN 将 AT2R 从细胞内位点易位至肾近曲小管细胞 (RPTC) 的顶端质膜 (AM)，并且这种易位被 NOC 消除。由于 D1R 激活通过腺苷酸环化酶/环磷酸腺苷 (cAMP) 信号通路诱导尿钠，因此我们探讨了该通路是否负责 AT2R 募集和 AT2R 介导的尿钠。 RI 联合输注腺苷酸环化酶激活剂毛喉素 (FSK) 和 3-异丁基-1-甲基黄嘌呤 (IBMX) 诱导尿钠排泄，这种排钠作用被 PD 或 NOC 消除，但不受特定 D1R 拮抗剂 SCH-23390 (SCH) 的影响。 FSK 和 IBMX 的共同管理还将 AT2R 转移到 RPTC 的 AM；此易位已被 NOC 废除，但不受 SCH 影响。结果表明，D1R 诱导的尿钠排泄需要 AT2R 以微管依赖性方式募集至 RPTC 的 AM，涉及腺苷酸环化酶/cAMP 信号通路。这些研究提供了关于肾脏 D1R 和 AT2R 协同作用促进体内 Na+ 排泄的机制的新见解。
Renal dopamine D1-like receptors (D1R) and angiotensin type-2 receptors (AT2R) are important natriuretic receptors counterbalancing angiotensin type-1 receptor-mediated tubular sodium (Na+) reabsorption. Here we explore the mechanisms of D1R and AT2R interaction in natriuresis. In uninephrectomized, Na+-loaded Sprague-Dawley rats, direct renal interstitial (RI) infusion of highly selective D1R agonist fenoldopam (FEN) induced a natriuretic response that was abolished by AT2R specific antagonist PD-123319 (PD) or by microtubule polymerization inhibitor nocodazole (NOC) but not by actin polymerization inhibitor cytochalasin D. By confocal microscopy and immuno-electron microscopy, FEN translocated AT2Rs from intracellular sites to the apical plasma membranes (AM) of renal proximal tubule cells (RPTCs) and this translocation was abolished by NOC. Since D1R activation induces natriuresis via an adenylyl cyclase/cyclic adenosine monophosphate (cAMP) signaling pathway, we explored whether this pathway is responsible for AT2R recruitment and AT2R-mediated natriuresis. RI co-infusion of adenylyl cyclase activator forskolin (FSK) and 3-isobutly-1-methylxanthine (IBMX) induced natriuresis that was abolished either by PD or NOC but was unaffected by specific D1R antagonist SCH-23390 (SCH). Co-administration of FSK and IBMX also translocated AT2Rs to the AMs of RPTCs; this translocation was abolished by NOC but was unaffected by SCH. The results demonstrate that D1R-induced natriuresis requires AT2R recruitment to the AMs of RPTCs in a microtubule-dependent manner involving an adenylyl cyclase/cAMP signaling pathway. These studies provide novel insights regarding the mechanisms whereby renal D1Rs and AT2Rs act in concert to promote Na+ excretion in vivo.