Endothelin - Mechanisms in Hypertension and Obesity

内皮素 - 高血压和肥胖的机制

基本信息

批准号：
9203632
负责人：
Joshua S Speed
金额：
$ 15.41万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9203632
关键词：
Address Adipocytes Adipose tissue Animal Model Animals Antihypertensive Agents Binding Blood Pressure Blood Vessels Body fat Cardiovascular Diseases Cardiovascular system Cause of Death Cells Chemotactic Factors Chronic Cost of Illness Data Defect Deposition Development Dietary Factors Disease Endothelin Endothelin A Receptor Endothelin-1 Environment Epidemic Fatty acid glycerol esters Functional disorder Goals Health High Fat Diet Homeostasis Human Hyperplasia Hypertension Immune In Vitro Individual Infiltration Inflammatory Response Insulin Intake Kidney Kidney Transplantation Knock-out Knockout Mice Lead Leptin Light Lipolysis LoxP-flanked allele Lymph Lymphatic Capillaries Lymphocyte Maintenance Mediating Mentors Metabolic Monocyte Chemoattractant Proteins Mus Obesity Osmolalities Pathway interactions Phase Physiological Plasma Play Production Rattus Receptor Activation Receptor Signaling Recruitment Activity Regulatory Pathway Renal function Role Signal Transduction Skin Testing Thinness Transplantation Vascular Cell Adhesion Molecule-1 Vascular Endothelial Cell Vascular Endothelial Growth Factor C Water blood pressure regulation cardiovascular risk factor combat db/db mouse density disorder risk enhancer binding protein experimental study extracellular human subject in vivo intercellular cell adhesion molecule interstitial lipid metabolism macrophage new therapeutic target receptor receptor binding receptor expression receptor function response salt intake salt sensitive hypertension transcription factor western diet

项目摘要

DESCRIPTION (provided by applicant): Mentored Phase: A long-term goal of the mentor, Dr. David Pollock, is to elucidate the role of ET-1 in salt sensitive hypertension. Recently, it was demonstrated that the interstitium of the skin is an important 4 reservoir for Na+, and defects in this storage capacity occurs in salt sensitive hypertension. While mechanisms are not fully understood, preliminary data suggest that vascular endothelial cell derived ET-1 plays a role in skin Na+ storage and clearance during a high salt intake. Therefore, the central hypothesis of the mentored phase is that increases in extrarenal vascular ET-1 influences blood pressure by increasing skin Na+ storage and clearance in response to high salt intake. To test this hypothesis, a vascular endothelial cell specific ET-1 knockout mouse (VEET KO) will be utilized. The first specific aim will determine if vascular ET-1 mediates pathways that regulate Na+ storage and clearance in response to a high salt intake. These include skin interstitial Na+ concentration, macrophages and lymphocytes, tonicity-responsive enhancer binding protein, vascular endothelial growth factor c, and lymph vessel hyperplasia. It is expected that increasing salt intake will lead to increases in each of these factors, and this will be abolished n VEET KO mice. Previous studies indicate that loss of any of these regulatory pathways results in salt sensitive hypertension, however VEET KO mice are hypotensive. It is believed that this is due to lack of ET-1 in renal vasculature, which would increase renal function will isolate the role of extrarenal vascular ET-1 in blood pressure regulation. Question 3 will address this question through the transplant of kidneys from control mice with intact vascular ET-1 into VEET KO mice, a manipulation that is expected to cause salt sensitive hypertension. Independent Phase: Several lines of evidence suggest that increased ET-1 mediates cardiovascular disease associated with obesity; however, preliminary data and previous studies on cultured adipocytes suggest that reduced ETA and/or increased ETB receptor activation on adipocytes produce a favorable environment that leads to obesity. Accordingly, the overall hypothesis of the independent phase is that an imbalance between ETA/ETB receptor signaling in adipocytes creates a favorable environment that leads to obesity. The second specific aim will determine if reductions in ETA and/or increases in ETB receptor expression and function in adipocytes can lead to obesity. This will be tested through in vitro experiments on cultured adipocytes as well as knocking out ETA receptors specifically in adipose tissue of mice. Specific aim 2 will also determine if reduced ETA and/or increases in ETB receptor expression and function occurs in obesity. This will be tested by determining if ET-1 receptor expression, binding, and signaling is altered in adipose tissue of lean and obese human subjects. The third specific aim will determine if metabolic and dietary factors, such as leptin and "western" diet, cause an imbalance of ET-1 signaling in adipose tissue. ET-1 production, as well as ET-1 receptor expression and binding will be determined in adipose tissue of ob/ob and db/db mice and animals chronically fed a high fat diet. The goals of the proposed studies will undoubtedly shed light on mechanistic pathways by which ET-1 influences blood pressure and obesity, two prevalent risk factors for cardiovascular disease.

描述（由申请人提供）：指导阶段：指导者 David Pollock 博士的长期目标是阐明 ET-1 在盐敏感性高血压中的作用。 Na+ 的重要 4 储存库，盐敏感性高血压中会出现这种储存能力的缺陷，虽然机制尚不完全清楚，但初步数据表明血管内皮细胞衍生的 ET-1 在皮肤 Na+ 储存中发挥作用。因此，指导阶段的中心假设是，肾外血管 ET-1 的增加通过增加皮肤 Na+ 的储存和清除来影响血压。将使用内皮细胞特异性 ET-1 敲除小鼠 (VEET KO)，第一个具体目标是确定血管 ET-1 是否介导响应高盐摄入而调节 Na+ 储存和清除的途径。 Na+、巨噬细胞和淋巴细胞、张力反应增强剂结合浓度蛋白、血管内皮生长因子C和淋巴管增生预计增加盐摄入量将导致这些因素的增加，而这将在VEET KO中消除。先前的研究表明，任何这些调节途径的缺失都会导致盐敏感性高血压，但 VEET KO 小鼠的血压较低，据信这是由于肾脏中缺乏 ET-1。血管系统，这会增加肾功能将隔离作用问题 3 将通过将具有完整血管 ET-1 的对照小鼠的肾脏移植到 VEET KO 小鼠中来解决这个问题，这种操作预计会导致盐敏感性高血压。多项证据表明，ET-1 增加会介导与肥胖相关的心血管疾病；然而，初步数据和之前对培养脂肪细胞的研究表明，脂肪细胞上 ETA 减少和/或 ETB 受体激活增加会产生有利的环境，从而导致因此，独立阶段的总体假设是脂肪细胞中 ETA/ETB 受体信号传导之间的不平衡创造了导致肥胖的有利环境。第二个具体目标将确定 ETA 的减少和/或 ETB 受体表达的增加。脂肪细胞中的功能和功能可能导致肥胖，这将通过体外培养的脂肪细胞实验进行测试。特异性敲除小鼠脂肪组织中的 ETA 受体还将确定肥胖中 ETA 是否减少和/或 ETB 受体表达和功能是否增加。第三个具体目标是确定瘦素和“西方”饮食等代谢和饮食因素是否会导致脂肪组织中 ET-1 信号失衡。 ET-1 的产生以及 ET-1 受体的表达和结合将在 ob/ob 和 db/db 小鼠以及长期喂养高脂肪饮食的动物的脂肪组织中进行测定。拟议研究的目标无疑将通过以下方式揭示机制途径。其中 ET-1 影响血压和肥胖，这是心血管疾病的两个常见危险因素。