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: 8198371
• 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/8198371
• 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. PUBLIC HEALTH RELEVANCE: Project Narrative Hypertension and its complications including chronic kidney disease (CKD), peripheral vascular disease, stroke and heart disease are a major public health problem. Despite improvements in the therapy of major risk factors, including hypertension, the incidence and prevalence of CKD continues to increase. Hypertension and CKD are particularly prevalent in the elderly, which constitute a large percentage of our veteran patient population. The co-morbid conditions associated with CKD are associated with a high mortality in this patient population. A better understanding of the mechanisms involved is critical in our efforts to develop novel strategies to prevent renal injury in hypertension, which would certainly result in improvements in morbidity and mortality in these patients.

描述（由申请人提供）： 项目摘要高血压及其并发症，包括慢性肾脏疾病（CKD），周围血管疾病，中风和心脏病是一个主要的公共卫生问题。盐敏感高血压会影响50％的高血压，并与增加最终器官损伤的风险增加有关，包括动脉粥样硬化，左心室肥大和肾脏疾病。尽管高血压，尤其是盐敏感高血压，被认为是CKD和心血管疾病的主要危险因素，但高血压导致终端器官损伤的机制尚不完全了解。 RAS的适应不良激活通过促进氧化应激，细胞外基质沉积，细胞增殖和炎症而在高血压最终器官损伤的发病机理中起重要作用。目前尚不清楚这些影响是否通过独立的机制发生，或者替代地发生，是否介导参与高血压中最终器官损伤发病机理的多种途径的激活。转录因子ETS-1已被确定为一个关键分子，可调节各种生长因子，趋化因子和粘附分子的血管表达。我们的中心假设是，ETS-1是一种常见的转录因子，可介导盐敏感性高血压中血管和肾损伤发病机理的促炎和纤维化途径的激活。我们将通过追求以下特定目的来检验我们的假设：目标1：表征NADPH氧化酶（NOX）衍生的ROS作为盐敏感性高血压中血管和肾脏ETS-1表达的介体的作用。该目标的工作假设是，纳德氧化酶（NOX）衍生的ROS在盐敏感高血压中作为ETS-1表达的介体起关键作用。我们将采用以下实验方法来完成此目标：1）我们将确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在盐敏感高血压中ETS-1表达的作用，3）我们将确定NADPH氧化酶在盐敏感大鼠中的NADPH氧化酶对ETS-1表达的作用。目标2：确定ETS-1作为盐敏感高血压中肾脏和血管损伤的介体的作用。该目标的工作假设是，ETS-1在高血压DAHL盐敏感大鼠中作为肾小球炎症和纤维化的介体起着至关重要的作用，这是人类盐敏感高血压的范式。我们将采用以下实验方法来完成此目标：1）我们将确定具有特定主要负肽对高血压DAHL盐敏感大鼠肾脏和血管炎症和纤维化的特定主导负肽对肾脏和血管炎症和纤维化的影响，2）我们将确定Eets-1阻断对促炎性粒细胞的影响对炎症性粒细胞的影响在炎症性壳中的影响。 AIM＃3：确定ETS-1通过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ANG II的肾脏炎症和纤维化的关键介体，并且这些作用通过增加的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此目标：我们将确定ETS-1对几个促值表达的影响 炎症性和促纤维性细胞因子，还将确定来自肾小球细胞中ETS-1对MCP-1和CTGF的转录调节。 公共卫生相关性： 项目叙事高血压及其并发症，包括慢性肾脏疾病（CKD），周围血管疾病，中风和心脏病是一个主要的公共卫生问题。尽管改善了主要危险因素的治疗，包括高血压，但CKD的发病率和患病率仍在增加。高血压和CKD在老年人中尤为普遍，这占我们老将患者人群的很大一部分。与CKD相关的合并症与该患者人群的死亡率高有关。对所涉及机制的更好理解对于制定新的防止高血压肾脏损伤的新策略至关重要，这无疑会改善这些患者的发病率和死亡率。