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Identification of a Primary Renal AT2 Receptor Defect in Spontaneously Hypertensive Rats.

自发性高血压大鼠原发性肾脏 AT2 受体缺陷的鉴定。

  • 影响因子:8.96
  • DOI:10.1161/CIRCRESAHA.119.316193
  • 作者列表:"Kemp BA","Howell NL","Gildea JJ","Keller SR","Carey RM
  • 发表时间:2020-01-30
Abstract

RATIONALE:Previous studies identified a defect in Ang III (angiotensin III [des-aspartyl-angiotensin II])-elicited ATR (Ang type-2 receptor)-mediated natriuresis in renal proximal tubule cells of spontaneously hypertensive rats (SHR).,OBJECTIVE:This study aimed to delineate in prehypertensive SHR kidneys the receptor or postreceptor defect causing impaired ATR signaling and renal sodium (Na) retention by utilizing the selective ATR agonist compound-21 (C-21).,METHODS AND RESULTS:Female 4-week-old Wistar Kyoto and SHR rats were studied after 24-hour systemic ATR (Ang II type-1 receptor) blockade. Left kidneys received 30-minute renal interstitial infusions of vehicle followed by C-21 (20, 40, and 60 ng/[kg·min], each dose 30 minutes). Right kidneys received vehicle infusions. In Wistar Kyoto, C-21 dose-dependently increased urine Na excretion from 0.023±0.01 to 0.064±0.02, 0.087±0.01, and 0.089±0.01 µmol/min (=0.008, <0.0001, and <0.0001, respectively) and renal interstitial fluid levels of ATR downstream signaling molecule cGMP (cyclic guanosine 3',5' monophosphate) from 0.91±0.3 to 3.1±1.0, 5.9±1.2 and 5.3±0.5 fmol/mL (=nonsignificant, <0.0001, and <0.0001, respectively). In contrast, C-21 did not increase urine Na excretion or renal interstitial cGMP in SHR. Mean arterial pressure was slightly higher in SHR but within the normotensive range and unaffected by C-21. In Wistar Kyoto, but not SHR, C-21 induced ATR translocation to apical plasma membranes of renal proximal tubule cells, internalization/inactivation of NHE-3 (sodium-hydrogen exchanger-3) and Na/KATPase (sodium-potassium-atpase) and phosphorylation of ATR-cGMP downstream signaling molecules Src (Src family kinase), ERK (extracellular signal-related kinase), and VASP (vasodilator-stimulated phosphoprotein). To test whether cGMP could bypass the natriuretic defect in SHR, we infused 8-bromo-cGMP. This restored natriuresis, Na transporter internalization/inactivation, and Src and VASP phosphorylation, but not apical plasma membrane ATR recruitment. In contrast, 8-bromo-cAMP administration had no effect on natriuresis or ATR recruitment in SHR.,CONCLUSIONS:The results demonstrate a primary renal proximal tubule cell ATR natriuretic defect in SHR that may contribute to the development of hypertension. Since the defect is abrogated by exogenous intrarenal cGMP, the renal cGMP pathway may represent a viable target for the treatment of hypertension. Visual Overview: An online visual overview is available for this article.

摘要

理由: 以前的研究确定了 Ang III (血管紧张素 III [去天冬氨酰-血管紧张素 II]) 的缺陷-引起 ATR (Ang 2 型受体) 介导自发性高血压大鼠 (SHR) 肾近端小管细胞的利钠尿。,目的: 本研究旨在描述高血压前期 SHR 肾脏中导致 ATR 信号和肾钠 (Na) 受损的受体或受体后缺陷利用选择性 ATR 激动剂化合物-21 (C-21) 保留,方法和结果: 对雌性 4 周龄 Wistar Kyoto 和 SHR 大鼠进行了 24 小时全身 ATR (Ang ⅱ 1 型受体) 阻断后的研究。左肾接受 30 分钟肾间质内输注溶剂,然后 C-21 (20 、 40 和 60 ng/[kg · min],每次剂量 30 分钟)。右肾接受溶剂输注。在 Wistar Kyoto,C-21 剂量依赖性增加尿 Na 排泄从 0.023 ± 0.01 到 0.064 ± 0.02,0.087 ± 0.01 和 0.089 ± 0.01 µ mol/min (= 0.008,<0.0001,和 <0.0001,分别) 和肾间质液水平的 ATR 下游信号分子 cGMP (环鸟苷 3 ',5' 一磷酸) 从 0.91 ± 0.3 到 3.1 ± 1.0, 5.9 ± 1.2 和 5.3 ± 0.5 fmol/mL (= 无显著性,分别 <0.0001 和 <0.0001)。相反,C-21 不增加 SHR 尿 Na 排泄或肾间质 cGMP。SHR 的平均动脉压略高,但在正常血压范围内,不受 C-21 影响。在 Wistar Kyoto,但不是 SHR,C-21 诱导 ATR 转位到肾近端小管细胞顶端质膜,内化/失活 NHE-3 (钠-氢交换体-3) 和 Na/KATPase (钠-钾-atp 酶) 和 ATR-cGMP 下游信号分子 Src (Src 家族激酶) 、 ERK (细胞外信号相关激酶) 的磷酸化,和 VASP (血管扩张刺激磷蛋白)。为了检测 cGMP 是否可以绕过 SHR 的利钠钠缺陷,我们输注了 8-溴-cGMP。这恢复了钠尿、 Na 转运蛋白内化/失活以及 Src 和 VASP 磷酸化,但没有恢复顶端质膜 ATR 募集。相比之下,8-溴-camp 给药对 SHR 的钠尿或 ATR 招募没有影响。,结论: 结果表明 SHR 的原发性肾近端小管细胞 ATR 钠尿肽缺陷可能与高血压的发生有关。由于外源性肾内 cGMP 可消除该缺陷,肾 cGMP 通路可能是治疗高血压的可行靶点。视觉概述: 本文提供了一个在线视觉概述。

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