Renal AT2 Receptors in Hypertension

项目总结/摘要 高血压（HT）影响约48%的美国人口。增加肾钠（Na+）潴留是一个主要的 有助于HT的发展。肾血管紧张素1型受体（AT 1 R），主要激活 由血管紧张素（Ang）II，是必要的和足够的诱导和维持HT在血管紧张素II输注。 肾近曲小管细胞（RPTC）中Na+重吸收增加是这种反应的主要决定因素。的 血管紧张素2型受体（AT 2 R）在Na+排泄和血压控制中的作用不太好 明白AT 2 R在成人肾脏中主要在RPTC中表达。我们过去的研究提供了证据， RPT AT 2 Rs在抑制肾脏Na+重吸收中的主要作用。最近，我们发现了AT 2 R的一个缺陷- 在自发性高血压大鼠（SHR）中介导的尿钠排泄早于HT， 直接肾脏给药环鸟苷酸（cGMP）。我们的研究结果表明，AT 2 R缺陷诱导的尿钠排泄 可能参与了SHR HT的发病机制。该项目的目标是（1）最终证明 利用我们新开发RPTC-AT 2 R缺陷小鼠，AT 2 R在BP控制中的作用，（2）鉴定下游 AT 2 R信号通路介导尿钠排泄，（3）表征SHR中原发性RPTC AT 2 R缺陷， 细胞和分子水平，以及（4）验证肾cGMP和蛋白磷酸酶2A（PP 2A）活化 作为HT的特异性治疗靶点。这些目标将在三个具体目标下实现：（1）测试 假设RPT AT 2 Rs是调节Na+排泄和血压所必需的;（2）为了检验RPT AT 2 Rs的作用， 假设蛋白磷酸酶2A（PP 2A）启动并维持RPTC AT 2 R信号传导， 尿钠排泄;和（3）检验肾内PP 2A激活和/或cGMP恢复的假设， 水平/信号转导可以使高血压SHR和RPTC选择性AT 2 R敲除小鼠的血压正常化。 该项目将采用最先进的体内细胞和分子技术相结合， 确定AT 2 R调节Na+排泄和BP的机制。这些研究将有助于确定 HT的病理生理学，并为治疗人类原发性HT的新型药物打开了大门。

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.