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

描述(由申请人提供)： 高血压及其并发症包括慢性肾脏疾病(CKD)、外周血管疾病、中风和心脏病是一个主要的公共卫生问题。盐敏感型高血压影响了50%的高血压患者，并增加了发生终末器官损伤的风险，包括动脉粥样硬化、左心室肥厚和肾脏疾病。尽管高血压，特别是盐敏感型高血压被认为是慢性肾脏病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不完全清楚。RAS的异常激活通过促进氧化应激、细胞外基质沉积、细胞增殖和炎症，在高血压终末器官损伤的发病机制中发挥重要作用。目前尚不清楚这些影响是通过独立的机制发生的，还是共同的转录机制介导了参与高血压终末器官损伤发病机制的多条途径的激活。转录因子Ets-1被认为是调节血管中多种生长因子、趋化因子和黏附分子表达的关键分子。我们的中心假设是Ets-1是一种常见的转录因子，它介导了促炎症和促纤维化途径的激活，参与了盐敏感型高血压血管和肾脏损伤的发病机制。我们将通过追求以下特定目标来验证我们的假设：目的1：表征NADPH氧化酶(NOX)衍生的ROS在盐敏感型高血压中作为血管和肾脏ETS-1表达的介体的作用。这一目的的工作假设是，NADPH氧化酶(NOX)来源的ROS在盐敏感型高血压中作为ETS-1表达的中介起着关键作用。我们将通过以下实验方法来完成这一目标：1)我们将鉴定上调高血压盐敏感大鼠Ets-1表达的肾小球和血管细胞；2)我们将确定降压对盐敏感高血压大鼠Ets-1表达的影响；3)我们将确定NADPH氧化酶衍生的ROS对盐敏感大鼠Ets-1表达的影响。目的：探讨Ets-1在盐敏感型高血压肾血管损伤中的作用。这一目标的工作假设是Ets-1在高血压Dahl盐敏感大鼠的肾小球炎症和纤维化中发挥关键作用，Dahl盐敏感大鼠是人类盐敏感性高血压的典范。我们将通过以下实验方法来实现这一目标：1)我们将确定具有特定显性显性负肽的Ets-1阻断对高血压Dahl盐敏感大鼠肾脏和血管炎症和纤维化的影响；2)我们将确定Ets-1阻断对高血压Dahl盐敏感大鼠促炎症细胞因子表达的影响。目的#3：确定Ets-1调控促炎症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Ang II反应中肾脏炎症和纤维化的关键介质，这些作用是通过Ets-1介导的促炎和促纤维化细胞因子的转录增加而发生的。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对几个PRO-1表达的影响。 此外，Ets-1还将决定Ets-1对系膜细胞中MCP-1和CTGF的转录调控。 公共卫生相关性： 项目简介高血压及其并发症包括慢性肾脏疾病(CKD)、外周血管疾病、中风和心脏病是一个主要的公共卫生问题。尽管包括高血压在内的主要危险因素的治疗有所改进，但慢性肾脏病的发病率和患病率仍在继续增加。高血压和慢性肾脏病在老年人中尤其普遍，他们在我们的退伍军人患者中占了很大比例。与CKD相关的合并症与该患者群体中的高死亡率相关。更好地了解所涉及的机制对于我们努力开发预防高血压肾损伤的新策略至关重要，这肯定会改善这些患者的发病率和死亡率。

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.