Renal AT2 Receptors in Hypertension

 描述(申请人提供)：血管紧张素(Ang)II，肾素-Ang系统(RAS)的主要传导肽，作用于两个主要受体：类型1(AT1R)和类型2(AT2R)。大多数血管紧张素转换酶II的作用是通过AT1Rs发生的，包括抗心绞痛。肾交叉移植研究表明，肾血管紧张素Ⅱ受体是血管紧张素转换酶II诱导和维持高血压的必要条件和充分条件，肾近端小管(RPT)Na+重吸收增加是这一反应的主要决定因素。相比之下，AT2Rs在控制Na+排泄和高血压中的作用还不是很清楚。我们实验室最近的研究为RPT AT2Rs在抑制Na+重吸收中的重要作用提供了证据。这些研究提供的证据表明，取代Ang II，Des-Aspartyl1-Ang II(Ang III)是诱导钠尿的首选AT2R激动剂。此外，我们现在有证据表明，自发性高血压大鼠(SHR)存在AT2R介导的钠尿缺陷，这种缺陷早于高血压，至少部分原因是肾内Ang III代谢加速。总体而言，我们的结果表明AT2R诱导的钠排泄是有缺陷的，并参与了SHR高血压的发病机制。本项目的总体目标是阐明自发性高血压患者AT2R介导的钠尿功能缺陷的机制。该项目将集中于三个具体目标：(1)检验AT2R介导的钠尿缺陷在自发性高血压发病机制中的重要作用的假说；(2)检验由于Ang III减少而导致自发性高血压患者钠尿受损的假说；(3)检验长期激活AT2R可以恢复正常的利钠和预防自发性高血压的假说。该项目将结合体内最先进的技术以及细胞和分子技术，包括肾内血管紧张素II和血管紧张素转换酶III的测量，以阐明AT2R在高血压钠排泄中的作用。这些研究将有助于确定人类原发性高血压的病理生理学，这是一种影响西方世界四分之一成年后人口的疾病。

 DESCRIPTION (provided by applicant): Angiotensin (Ang) II, the primary transducer peptide of the renin-Ang system (RAS), acts at two major receptors: type-1 (AT1R) and type-2 (AT2R). The majority of Ang II actions occur via AT1Rs, including antinatriuresis. Renal cross-transplantation studies have demonstrated that renal AT1Rs are both necessary and sufficient for the induction and sustainability of hypertension during Ang II infusion and that increased Na+ reabsorption in the renal proximal tubule (RPT) is the major determinant of this response. In contrast, the role of AT2Rs in the control of Na+ excretion and hypertension is less clearly defined. Recent studies from our laboratory have provided evidence for a major role of RPT AT2Rs in the inhibition of Na+ reabsorption. These studies have provided evidence that, instead of Ang II, des-aspartyl1-Ang II (Ang III) is the preferred AT2R agonist inducing natriuresis. Furthermore, we now have evidence for a defect in AT2R-mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates the hypertension and is due, at least in part, to accelerated intrarenal Ang III metabolism. Overall, our results suggest that AT2R-induced natriruesis is defective and contributes to the pathogenesis of hypertension in SHR. The overall goal of this project is to elucidate the mechanisms of defective AT2R-mediated natriuresis in SHR. The project will focus on three specific aims: (1) To test the hypothesis that defective AT2R-mediated natriuresis is important in the pathogenesis of HT in SHR; (2) To test the hypothesis that impaired natriuresis in SHR is due to reduction of Ang III; and (3) To test the hypothesis that chronic AT2R activation can restore normal natriuresis and prevent HT in SHR. The project will apply a combination of state-of-the-art in vivo and cell and molecular techniques, including intrarenal Ang II and III measurements, to clarify the role of the AT2R in sodium excretion in hypertension. These studies will help define the pathophysiology of human primary hypertension, a disorder affecting one-quarter after adult population in the Western world.