Molecular Mechanism of PGE2 Receptor Pressor Effects

描述（由申请人提供）：前列腺素E2 （PGE2）调节血压，它可以发挥血管加压或血管抑制作用。这些生理上相反的作用可以部分解释为四种PGE2受体的存在，称为e -前列腺素（EP）受体EP1至EP4。EP1和EP3受体主要介导升压反应，而EP2和EP4受体介导降压反应。我们将利用EP1和EP3缺失小鼠模型来研究PGE2的升压作用。我们将确定血管紧张素II与EP1激活相互作用的机制。我们将进一步研究EP3受体的作用机制，与EP1受体相比，EP3受体似乎具有完全不同的特性和加压作用机制。我们假设这两种受体以不同的方式作用于不同的靶标，并可能协同产生PGE2的升压作用。由于EP1受体已被证明介导血管紧张素II和肾素-血管紧张素系统的一些升压作用，我们假设EP1可能介导肾素-血管紧张素系统引起的肾纤维化和慢性肾脏疾病的作用。为了调查这些相关的假设，我们将承担以下三个具体目标：探讨EP1受体升压作用的分子机制。专项目的2：确定EP3受体升压作用的分子机制。特异性目的3：确定EP1或EP3受体阻断是否会预防或减轻慢性肾脏疾病的进展。本项目将评估两种PGE2受体的作用机制及其在肾纤维化发展过程中对血压升高的贡献。体外研究将重点关注AT1血管紧张素受体和PGE2 EP受体的下游受体信号转导，以研究受体协同作用的证据。研究将包括小鼠糖尿病肾病模型，5/6肾切除术和血管紧张素诱导的高血压，以研究肾脏损害的潜在机制。

DESCRIPTION (provided by applicant): Prostaglandin E2 (PGE2) regulates blood pressure, where it can exert either vasopressor or vasodepressor effects. These physiologically opposing effects can be explained in part by the existence of four PGE2 receptors, designated the E-Prostanoid (EP) receptors EP1 through EP4. The EP1 and EP3 receptors primarily mediate the pressor response, while the EP2 and EP4 receptors mediate the depressor response. We will investigate the role of the pressor effects of PGE2 utilizing EP1 and EP3 null mouse models. We will determine the mechanism by which angiotensin II interacts with EP1 activation. We will further investigate the mechanism of action of the EP3 receptor, which appears to have has quite distinct properties and mechanism of pressor action compared to the EP1 receptor. We hypothesize that the two receptors act in distinct manners on disparate targets and may synergize to produce the pressor effect of PGE2. Because the EP1 receptor has been demonstrated to mediate some of the pressor effects of angiotensin II and the renin-angiotensin-system, we hypothesize that EP1 may mediate renin-angiotensin-system evoked effects on renal fibrosis and chronic kidney disease. To investigate these related hypotheses, we will undertake the following three Specific Aims: Specific aim 1. To determine the molecular mechanism of EP1 receptor pressor effects. Specific aim 2: To determine the molecular mechanism of EP3 receptor pressor effects. Specific aim 3: To determine whether EP1 or EP3 receptor blockade will prevent or attenuate the progression of chronic kidney disease. PUBLIC HEALTH RELEVANCE This project will assess the mechanism of action of two PGE2 receptors and their contribution to elevated blood pressure in the development of renal fibrosis. In vitro studies will focus on the downstream receptor signal transduction of AT1 angiotensin receptor and PGE2 EP receptors to investigate evidence of receptor synergy. Studies will include mouse models of diabetic nephropathy, 5/6 nephrectomy and angiotensin induced hypertension to examine potential mechanisms of renal damage.