Prostaglandin E2 and Regulation of Kidney Function

描述（由申请人提供）：在前列腺素中，PGE2的独特之处在于它的作用是由四种不同的E-前列腺素（EP）受体异构体组成的家族介导的。这些受体（EP1-4）具有不同的组织分布和不同的信号通路，为PGE2在肾脏和其他组织中的一系列功能提供了分子基础。因此，PGE2的产生对血压的影响可能因其合成位点和EP受体激活的模式而异。例如，我们发现EP4受体主要负责通过黄斑致密通路触发肾小球旁器（JGA）肾素的表达。此外，我们使用两种新型小鼠模型进行的初步研究表明：(1)内皮细胞特异性缺失EP4受体可减弱血管收缩剂对血管紧张素II的反应；(2)EP4受体的普遍消除可显著抵抗血管紧张素II依赖性高血压。综上所述，这些发现表明EP4受体通过激活RAS、促进血管紧张素II的高血压作用和增强外周血管阻力等独立机制促进血压升高。本文提出的研究目的是精确定义与EP4受体相关的可能参与高血压发病机制的机制。具体来说，我们将使用转基因小鼠模型和EP4受体拮抗剂，为EP4受体在心血管调节中的作用提供新的见解。为此，我们将追求以下具体目标：(1)确定肾脏EP4受体在高血压发病机制中的具体作用。(2)探讨内皮细胞和血管平滑肌细胞（VSMCs）中EP4受体池对血压控制的影响。(3)明确集管中EP4受体在血压和肾排泄功能调节中的作用。(4)检测EP4受体作为高血压治疗靶点的潜力。这些实验的长期目标是确定EP4受体作为高血压新治疗靶点的潜力。

DESCRIPTION (provided by applicant): Among the prostanoids, PGE2 is unique in that its actions are mediated by a family of four different E- prostanoid (EP) receptor isoforms. These receptors (EP1-4) have distinct tissue distributions and couple to disparate signaling pathways, providing a molecular basis for the range of functions attributed to PGE2 in the kidney and in other tissues. Thus, the impact of PGE2 generation on blood pressure may differ depending on its sites of synthesis and the resulting pattern of EP receptor activation. For example, we showed that the EP4 receptor is primarily responsible for triggering expression of renin at the juxtaglomerular apparatus (JGA) via the macula densa pathway. Furthermore, our preliminary studies using two novel mouse models show that: (1) cell-specific deletion of EP4 receptors in endothelium attenuates vasoconstrictor responses to angiotensin II and (2) generalized elimination of EP4 receptors confers substantial resistance to angiotensin II-dependent hypertension. Taken together, these findings suggest a consistent function for the EP4 receptor to promote increased blood pressure through independent mechanisms that include activating the RAS, promoting hypertensive effects of angiotensin II, and enhancing peripheral vascular resistance. The objective of the studies proposed here is to precisely define mechanisms linked to the EP4 receptor that may contribute to the pathogenesis of hypertension. Specifically, we will use genetically modified mouse models and EP4 receptor antagonists to provide new insights into the role of EP4 receptors in cardiovascular regulation. To this end, we will pursue the following Specific Aims: (1) To determine the specific role of EP4 receptors in the kidney in the pathogenesis of hypertension. (2) To establish the impact of EP4 receptor pools in the endothelium and vascular smooth muscle cells (VSMCs) on blood pressure control. (3) To define the contribution of EP4 receptors in the collecting duct to the regulation of blood pressure and renal excretory function. (4) To test the potential of the EP4 receptor as a therapeutic target in hypertension. The long-term goal of these experiments is to determine the potential of the EP4 receptor as a novel therapeutic target in hypertension. PUBLIC HEALTH RELEVANCE: High blood pressure is a major public health problem in the United States affecting more than 50 million individuals. Our proposal explores a novel pathway promoting the development of hypertension: activation of the EP4 receptor for prostaglandin E2. We will explore the mechanism used by the EP4 receptor to raise blood pressure and will define its potential utility as a therapeutic target for the treatment of hypertension.