ETS-1 and Vascular and Renal Injury in Salt Sensitive Hypertension

ETS-1 与盐敏感性高血压中的血管和肾脏损伤

• 批准号: 8391638
• 负责人: EDGAR A JAIMES
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391638
• 关键词: Affect; Aldosterone; Angiotensin II; Aorta; Atherosclerosis; Biological Availability; Blood Vessels; CCL2 gene; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell Proliferation; Cells; Chronic Kidney Failure; Dahl Hypertensive Rats; Data; Deposition; Developed Countries; Development; Disease susceptibility; Dominant-Negative Mutation; Elderly; Enzymes; Extracellular Matrix; Fibrosis; Generations; Genes; Genetic Transcription; Growth Factor; Heart Diseases; Human; Hypertension; Hypotension; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injury; Kidney; Kidney Diseases; Knowledge; Left Ventricular Hypertrophy; Mediating; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; NADPH Oxidase; Nitric Oxide; Organ; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral Vascular Diseases; Play; Prevalence; Public Health; Rattus; Reactive Oxygen Species; Renin-Angiotensin System; Research; Risk; Risk Factors; Role; Stroke; Testing; Transcriptional Regulation; United States; Up-Regulation; Veterans; Work; base; chemokine; connective tissue growth factor; cytokine; hypertension treatment; in vivo; kidney vascular structure; mesangial cell; mortality; novel strategies; novel therapeutics; patient population; prevent; public health relevance; response; salt sensitive; transcription factor; vascular inflammation; vasoconstriction

DESCRIPTION (provided by applicant): Project Summary Hypertension and its complications including chronic kidney disease (CKD), peripheral vascular disease, stroke and heart disease are a major public health problem. Salt sensitive hypertension affects 50% of hypertensives and is associated with an increased risk for the development of end-organ injury including atherosclerosis, left ventricular hypertrophy and renal disease. Although hypertension, and especially salt sensitive hypertension, is recognized as a major risk factor for CKD and cardiovascular disease, the mechanisms by which hypertension causes end organ injury are not completely understood. Maladaptive activation of RAS plays an important role in the pathogenesis of end organ injury in hypertension by promoting oxidative stress, extracellular matrix deposition, cell proliferation and inflammation. It is not clear whether these effects occur via independent mechanisms, or alternatively, whether common transcriptional mechanisms mediate the activation of multiple pathways that participate in the pathogenesis of end-organ injury in hypertension. The transcription factor ETS-1 has been identified as a critical molecule that regulates the vascular expression of a variety of growth factors, chemokines and adhesion molecules. Our central hypothesis is that ETS-1 is a common transcription factor that mediates the activation of pro-inflammatory and pro-fibrotic pathways involved in the pathogenesis of vascular and renal injury in salt sensitive hypertension. We will test our hypothesis by pursuing the following specific Aims: Aim 1: Characterize the role of NADPH oxidase (NOX) derived ROS as mediators of vascular and renal ETS-1 expression in salt sensitive hypertension. The working hypothesis for this aim is that NADPH oxidase (NOX) derived ROS play a critical role as mediators of ETS-1 expression in salt sensitive hypertension. We will use the following experimental approach to take this aim to completion: 1) We will identify the glomerular and vascular cells that up-regulate ETS-1 in hypertensive salt sensitive rats; 2) We will determine the role of blood pressure lowering on ETS-1 expression in salt sensitive hypertension and 3) We will determine the role of NADPH oxidase derived ROS on ETS-1 expression in salt sensitive rats. Aim 2: To identify the role of ETS-1 as mediator of renal and vascular injury in salt sensitive hypertension. The working hypothesis for this aim is that ETS-1 plays a critical role as mediator of glomerular inflammation and fibrosis in the hypertensive Dahl salt sensitive rat, a paradigm of salt sensitive hypertension in humans. We will use the following experimental approach to take this aim to completion: 1) We will determine the effects of ETS-1 blockade with a specific dominant negative peptide on renal and vascular inflammation and fibrosis in hypertensive Dahl salt sensitive rats and 2) we will determine the effects of ETS-1 blockade on the expression of pro-inflammatory cytokines in hypertensive Dahl salt sensitive rats. Aim #3: Identify the molecular mechanisms by which ETS-1 modulate the expression of pro-inflammatory and pro-fibrotic genes. Our working hypothesis is that ETS-1 is a critical mediator of renal inflammation and fibrosis in response to Ang II and that these effects occur via increased ETS-1 mediated transcription of pro-inflammatory and pro-fibrotic cytokines. We will use the following experimental approach to take this aim to completion: We will determine the effects of ETS-1 on the expression of several pro- inflammatory and pro-fibrotic cytokines and will also determine the transcriptional regulation of MCP-1 and CTGF by ETS-1 in mesangial cells.

描述（由申请人提供）： 高血压及其并发症，包括慢性肾脏病（CKD）、外周血管疾病、中风和心脏病，是一个重大的公共卫生问题。盐敏感性高血压影响50%的高血压患者，并与终末器官损伤（包括动脉粥样硬化、左心室肥大和肾脏疾病）发生的风险增加相关。虽然高血压，特别是盐敏感性高血压，被认为是CKD和心血管疾病的主要危险因素，但高血压导致终末器官损伤的机制尚未完全了解。RAS的不适应性激活通过促进氧化应激、细胞外基质沉积、细胞增殖和炎症反应在高血压终末器官损伤的发病机制中起重要作用。目前尚不清楚这些作用是否通过独立的机制发生，或者共同的转录机制是否介导了参与高血压终末器官损伤发病机制的多种途径的激活。转录因子ETS-1被认为是调节多种生长因子、趋化因子和粘附分子在血管中表达的关键分子。我们的中心假设是ETS-1是一种常见的转录因子，其介导参与盐敏感性高血压中血管和肾损伤发病机制的促炎和促纤维化途径的激活。我们将通过追求以下具体目标来测试我们的假设：目标1：表征盐敏感性高血压中NADPH氧化酶（NOX）衍生的ROS作为血管和肾脏ETS-1表达的介导物的作用。这一目标的工作假设是，NADPH氧化酶（NOX）衍生的活性氧在盐敏感性高血压中作为ETS-1表达的介导剂发挥关键作用。我们将使用以下实验方法来完成这一目标：1）我们将鉴定高血压盐敏感大鼠中上调ETS-1的肾小球和血管细胞; 2）我们将确定降低血压对盐敏感性高血压中ETS-1表达的作用; 3）我们将确定盐敏感大鼠中NADPH氧化酶衍生的ROS对ETS-1表达的作用。目的2：探讨ETS-1在盐敏感性高血压肾血管损伤中的作用。为此目的的工作假设是ETS-1在高血压Dahl盐敏感大鼠（人类盐敏感性高血压的范例）中作为肾小球炎症和纤维化的介体起关键作用。我们将使用以下实验方法来完成该目的：1）我们将确定用特异性显性负性肽阻断ETS-1对高血压Dahl盐敏感大鼠中的肾和血管炎症和纤维化的影响，和2）我们将确定ETS-1阻断对高血压Dahl盐敏感大鼠中促炎细胞因子表达的影响。目的#3：确定ETS-1调节促炎和促纤维化基因表达的分子机制。我们的工作假设是ETS-1是响应于Ang II的肾脏炎症和纤维化的关键介质，并且这些作用通过增加ETS-1介导的促炎和促纤维化细胞因子的转录而发生。我们将使用以下实验方法来完成这一目标：我们将确定ETS-1对几种前体蛋白表达的影响。 炎症和促纤维化细胞因子，并且还将决定系膜细胞中ETS-1对MCP-1和CTGF的转录调节。