Molecular Mechanism of PGE2 Receptor Pressor Effects

PGE2 受体升压效应的分子机制

• 批准号: 7850083
• 负责人: RICHARD M. BREYER
• 金额: $ 2.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7850083
• 关键词: Accounting; Acute; Angiotensin II; Angiotensins; Arachidonic Acids; Attenuated; Blood Pressure; Blood Vessels; Cells; Chronic Kidney Failure; Data; Development; Diabetic Nephropathy; Dinoprostone; Disodium Salt Nitroprusside; Double Effect; EP4 receptor; Fibrosis; Gene Targeting; Genetic; Hypertension; In Vitro; Infusion procedures; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Knockout Mice; Mediating; Molecular; Nephrectomy; Phenotype; Phenylephrine; Physiological; Property; Prostaglandins; Receptor Signaling; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Role; Signal Transduction; Transgenic Mice; Vasoconstrictor Agents; Work; base; blood pressure regulation; human WFDC2 protein; hypertension treatment; in vivo; insight; mouse model; novel; pressure; prevent; prostaglandin EP3 receptor; prostanoid receptor EP1; public health relevance; receptor; response

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.

描述（由申请人提供）：前列腺素E2（PGE2）调节血压，可以在其中发挥加压剂或血管抑制剂效应。这些在生理上相反的作用可以部分用四种PGE2受体的存在来解释，这些PGE2受体被指定为E-prostanoid（EP）受体EP1至EP4。 EP1和EP3受体主要介导压压反应，而EP2和EP4受体介导抑制剂反应。我们将研究利用EP1和EP3 NULL小鼠模型的PGE2的压力效应的作用。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受体的作用机理，与EP1受体相比，该受体似乎具有截然不同的特性和机理。我们假设这两个受体以不同的方式作用于不同的靶标，并且可以协同作用以产生PGE2的施加效应。由于EP1受体已被证明可以介导血管紧张素II和肾素 - 血管紧张素系统的一些施加作用，因此我们假设EP1可能介导肾素 - 血管紧张素 - 系统引起对肾脏纤维化和慢性肾脏病的影响。为了研究这些相关的假设，我们将承担以下三个特定目的：特定目的1。确定EP1受体施加效应的分子机制。具体目标2：确定EP3受体施加效应的分子机制。特定目标3：确定EP1或EP3受体阻滞是否会预防或减弱慢性肾脏疾病的进展。公共卫生相关性该项目将评估两种PGE2受体的作用机理，以及它们对肾脏纤维化发展中血压升高的贡献。体外研究将集中于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。研究将包括糖尿病肾病，5/6肾切除术和血管紧张素诱导高血压的小鼠模型，以检查肾损伤的潜在机制。