Molecular Mechanism of PGE2 Receptor Pressor Effects

描述(申请人提供)：前列腺素E2(PGE2)调节血压，在那里它可以发挥血管升压或血管降压作用。这些生理上相反的效应可以部分解释为四个PGE2受体的存在，称为E-前列腺素(EP)受体EP1到EP4。EP1和EP3受体主要介导升压反应，而EP2和EP4受体则介导降压反应。我们将利用EP1和EP3缺失的小鼠模型来研究PGE2升压效应的作用。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受体似乎具有非常不同的升压作用特性和机制。我们推测，这两种受体以不同的方式作用于不同的靶点，并可能协同作用，产生PGE2的升压效应。由于EP1受体已被证实介导了血管紧张素II和肾素-血管紧张素系统的部分升压作用，我们推测EP1可能介导肾素-血管紧张素系统在肾纤维化和慢性肾脏疾病中的诱发效应。为了研究这些相关的假说，我们将承担以下三个具体目的：具体目的1.确定EP1受体升压作用的分子机制。具体目的2：探讨EP3受体升压作用的分子机制。具体目标3：确定阻断EP1或EP3受体是否能预防或延缓慢性肾脏疾病的进展。公共卫生相关性本项目将评估两种PGE2受体的作用机制，以及它们在肾纤维化发展过程中对高血压的贡献。体外研究将集中于AT1血管紧张素受体和PGE2EP受体下游受体的信号转导，以探讨受体协同作用的证据。研究将包括糖尿病肾病的小鼠模型、5/6肾切除术和血管紧张素诱导的高血压，以检查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.