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: 8045940
• 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/8045940
• 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; 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; NADPH Oxidase; Nitric Oxide; Organ; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathway interactions; 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; Work; base; chemokine; connective tissue growth factor; cytokine; hypertension treatment; in vivo; kidney vascular structure; mesangial cell; mortality; novel strategies; novel therapeutics; prevent; 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）：