Renal AT2 Receptors in Hypertension

项目摘要/摘要 高血压影响着大约48%的美国人口。肾脏钠(Na+)滞留增加是一个主要原因 肾血管紧张素-1受体(AT1R)主要被激活 血管紧张素(Ang)II是诱导和维持Ang II输注过程中高血压的必要条件和充分条件。 肾脏近端小管细胞(RPTC)对Na+的重吸收增加是这种反应的主要决定因素。这个 血管紧张素2型受体(AT2R)在Na+排泄和血压控制中的作用还不是很清楚 明白了。AT2Rs主要在成人肾脏中表达，主要在RPTC中表达。 RPT AT2Rs在抑制肾脏Na+重吸收中的主要作用。最近，我们发现了AT2R的一个缺陷- 自发性高血压大鼠(SHR)介导性钠尿先于高血压并可被 肾直接给药环鸟苷酸(CGMP)。我们的结果表明，AT2R缺陷导致的钠尿症 可能与自发性高血压的发病机制有关。本项目的目标是(1)最终证明 利用我们新开发的RPTC-AT2R缺陷小鼠，AT2Rs在血压控制中的作用，(2)识别下游 AT2R信号通路介导的钠尿，(3)自发性高血压大鼠原发性RPTC AT2R缺陷(S)的特征 细胞和分子水平，以及(4)验证肾脏cGMP和蛋白磷酸酶2A(PP2A)的激活 作为治疗高血压的特异性靶点。这些目标将在三个具体目标下实现：(1)测试 假设RPT AT2Rs是调节Na+排泄和血压所必需的；(2)测试 蛋白磷酸酶2A(PP2A)启动和维持RPTC AT2R信号诱导 以及(3)检验肾内PP2A激活和/或cGMP恢复的假设 水平/信号可以使高血压SHR和RPTC选择性AT2R基因敲除小鼠的血压正常化。 该项目将应用体内最先进的技术以及细胞和分子技术来 确定AT2R调节Na+排泄和血压的机制。这些研究将有助于定义 甲状旁腺功能障碍的病理生理机制，并为治疗人类原发性甲状旁腺功能障碍的新的药物类别打开大门。

PROJECT SUMMARY/ABSTRACT Hypertension (HT) affects ~48% of the US population. Increased renal sodium (Na+) retention is a major contributor to the development of HT. The renal angiotensin type-1 receptor (AT1R), activated predominantly by angiotensin (Ang) II, is both necessary and sufficient for inducing and sustaining HT during Ang II infusion. Increased Na+ reabsorption in renal proximal tubule cells (RPTC) is a major determinant of this response. The role of the angiotensin type-2 receptor (AT2R) in Na+ excretion and blood pressure (BP) control is less well understood. AT2Rs are expressed in adult kidneys primarily in RPTC. Our past studies provided evidence for a major role of RPT AT2Rs in the inhibition of renal Na+ reabsorption. Recently, we identified a defect in AT2R- mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates HT and can be circumvented by direct renal administration of cyclic GMP (cGMP). Our results suggest that defective AT2R-induced natriuresis may contribute to the pathogenesis of HT in SHR. The goals of this project are to (1) conclusively demonstrate the role of AT2Rs in BP control using our newly developed RPTC-AT2R deficient mice, (2) identify downstream AT2R signaling pathways mediating natriuresis, (3) characterize the primary RPTC AT2R defect(s) in SHR at the cellular and molecular levels, and (4) validate renal cGMP and protein phosphatase 2A (PP2A) activation as specific therapeutic targets for HT. These goals will be addressed under three specific aims: (1) To test the hypothesis that RPT AT2Rs are required for the regulation of Na+ excretion and blood pressure; (2) To test the hypothesis that protein phosphatase 2A (PP2A) initiates and sustains RPTC AT2R signaling to induce natriuresis; and (3) To test the hypothesis that intrarenal PP2A activation and/or restoration of cGMP levels/signaling can normalize blood pressure in hypertensive SHR and RPTC-selective AT2R knockout mice. The project will apply a combination of state-of-the-art in vivo and cellular and molecular techniques to determine mechanisms by which AT2R regulates Na+ excretion and BP. These studies will help define the pathophysiology of HT and open the door to new classes of drugs for the treatment of human primary HT.