Endothelin - Mechanisms in Hypertension and Obesity

内皮素 - 高血压和肥胖的机制

• 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
• 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

 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：导师David Pollock博士的长期目标是阐明ET-1在盐敏感型高血压中的作用。最近的研究表明，皮肤间质是一个重要的钠离子储存库，盐敏感型高血压患者会出现这种储存能力的缺陷。虽然机制还不完全清楚，但初步数据表明，血管内皮细胞衍生的ET-1在高盐摄入期间皮肤Na+的储存和清除中发挥了作用。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对高盐摄入的Na+储存和清除来影响血压。为了验证这一假设，将利用血管内皮细胞特异性ET-1基因敲除小鼠(VEET KO)。第一个特定的目标将确定血管ET-1是否介导调节Na+储存和清除的通路，以响应高盐摄入量。这些包括皮肤间质Na+浓度、巨噬细胞和淋巴细胞、紧张性反应增强子结合蛋白、血管内皮生长因子c和淋巴管增生。预计盐摄入量的增加将导致这些因素中的每一个都增加，这在VEET KO小鼠中将被取消。先前的研究表明，这些调节通路中的任何一个的丢失都会导致盐敏感型高血压，但VEET KO小鼠是低血压的。据认为，这是由于肾血管中缺乏ET-1，这会使肾功能增强而起到隔离作用 肾外血管ET-1在血压调节中的作用问题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小鼠来解决这个问题，这种操作预计会导致盐敏感型高血压。独立期：多条证据表明，ET-1的增加与肥胖相关的心血管疾病有关；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导致肥胖的有利环境。因此，独立阶段的总体假设是，脂肪细胞中ETA/ETB受体信号之间的失衡创造了导致肥胖的有利环境。第二个特定目标将确定脂肪细胞中ETA减少和/或ETB受体表达和功能增加是否会导致肥胖。这将通过培养的脂肪细胞的体外实验以及 敲除小鼠脂肪组织中的ETA受体。特定的目标2还将确定肥胖是否发生ETA减少和/或ETB受体表达和功能增加。这将通过确定瘦身和肥胖受试者的脂肪组织中ET-1受体的表达、结合和信号是否发生变化来进行测试。第三个具体目标将确定代谢和饮食因素，如瘦素和“西方”饮食，是否导致脂肪组织中ET-1信号的失衡。将在ob/ob和db/db小鼠和长期喂养高脂饮食的动物的脂肪组织中测定ET-1的产生以及ET-1受体的表达和结合。这项拟议研究的目标无疑将阐明ET-1影响血压和肥胖的机制，这是心血管疾病的两个普遍风险因素。