Molecular Mechanism of PGE2 Receptor Pressor Effects

描述（由申请人提供）：前列腺素E2（PGE 2）调节血压，可发挥血管加压或血管降压作用。这些生理上相反的作用可以部分地通过四种PGE 2受体的存在来解释，所述四种PGE 2受体被命名为E-前列腺素（EP）受体EP 1至EP 4。EP 1和EP 3受体主要介导升压反应，而EP 2和EP 4受体介导降压反应。我们将利用EP 1和EP 3缺失小鼠模型研究PGE 2的升压作用。我们将确定血管紧张素II与EP 1激活相互作用的机制。我们将进一步研究EP 3受体的作用机制，与EP 1受体相比，EP 3受体似乎具有非常独特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，并可能协同产生PGE 2的升压作用。由于EP 1受体已被证明介导血管紧张素II和肾素-血管紧张素系统的升压作用，我们假设EP 1可能介导肾素-血管紧张素系统诱发的肾纤维化和慢性肾脏疾病的影响。为了研究这些相关的假设，我们将进行以下三个具体目标：具体目标1.探讨EP 1受体升压作用的分子机制。具体目的2：探讨EP 3受体升压作用的分子机制。具体目标3：确定EP 1或EP 3受体阻断剂是否会预防或减缓慢性肾脏疾病的进展。本项目将评估两种PGE 2受体的作用机制及其在肾纤维化发展中对血压升高的作用。体外研究将集中于AT 1血管紧张素受体和PGE 2 EP受体的下游受体信号转导，以研究受体协同作用的证据。研究将包括糖尿病肾病、5/6肾切除术和血管紧张素诱导的高血压的小鼠模型，以检查肾损伤的潜在机制。

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.