The Molecular Physiology of Renalase

肾酶的分子生理学

基本信息

批准号：
7917422
负责人：
Gary V. Desir
金额：
$ 32.11万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-18 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7917422
关键词：
Acute Adrenergic Receptor Affect American Animal Model Animals Anterior Blood Blood Pressure Cardiac Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Catecholamines Chronic Kidney Failure Dialysis procedure Dopamine End stage renal failure Endocrine Enzymes Epinephrine Essential Hypertension Gene Expression Genes Genetic Databases Glomerular Filtration Rate Heart Heart Diseases Hormones Hypertension Hypotension Kidney Kidney Diseases Knockout Mice Left Life Ligation Light Link Mediating Methods Molecular Morbidity - disease rate Mus Myocardial Myocardial Ischemia Norepinephrine Organ Oxidative Stress Pathogenesis Pathway interactions Patients Phenotype Physiology Plasma Play Population Pressoreceptors Proteins Rattus Relative (related person)Renal Replacement Therapy Renal function Risk Role Single Nucleotide Polymorphism Skeletal Muscle Small Intestines Sympathetic Nervous System Testing Therapeutic Transgenic Animals Transplantation amine oxidase blood pressure regulation calcification cardiovascular risk factor falls in vivo inhibitor/antagonist man mortality novel patient population protein function public health relevance uptake

项目摘要

DESCRIPTION (provided by applicant): Approximately 22 millions Americans suffer from chronic kidney disease (CKD), and 300,000 require renal replacement therapy for end stage kidney disease (ESRD). CKD patients are at significantly greater risk of having both fatal and non-fatal cardiovascular complications Renal replacement therapy prolongs the life of patients with ESRD, however, cardiovascular morbidity and mortality remains extremely high in the dialysis population. The propensity patients with kidney disease develop cardiac disease has been linked to a number of factors including heightened sympathetic tone, increased oxidative stress, and widespread arterial calcification. To investigate the pathogenesis of cardiac disease in CKD/ESRD, we hypothesized that the kidney's endocrine function was incompletely understood, that the organ secretes proteins that regulate cardiac function, and that these proteins could be identified using a combination of molecular methods and genetic database analysis. That effort led to the discovery of renalase, a novel FAD-dependent amine oxidase that is expressed in kidney, and heart. It is secreted into blood, and degrades circulating catecholamines. Renalase administration lowers blood pressure, and also protects against acute myocardial ischemia. Blood levels correlate positively with renal function, and patients with CKD and ESRD have low renalase levels. The molecular details of the renalase pathway are beginning to emerge, and we find that catecholamines regulate renalase gene expression, secretion and enzymatic activation. We hypothesize that renalase plays a key role in regulating catechlolamines levels and sympathetic activity, and that renalase deficiency in kidney disease results in heightened sympathetic tone, hypertension and increased cardiovascular risk. In the context of these findings and of the overall hypothesis, we propose to examine how catecholamines and/or blood pressure regulate blood renalase activity in vivo. We will study the mechanisms that mediate hypertension in the renalase knockout mouse. We will use transgenic animals to determine the specific contribution of the kidney to the renalase pathway. These studies will significantly enhance our understanding of the renalase pathway, and will begin to shed light on renalase's role in the pathogenesis of hypertension and cardiovascular complications associated with kidney disease. PUBLIC HEALTH RELEVANCE: Twenty millions Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered hormone that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. Renalase itself or components of the renalase pathway may offer valuable therapeutic options for patients with kidney disease.

描述（由申请人提供）：大约 2200 万美国人患有慢性肾病 (CKD)，其中 300,000 人需要肾脏替代治疗来治疗终末期肾病 (ESRD)。 CKD 患者发生致命和非致命心血管并发症的风险明显更高。肾脏替代治疗可延长 ESRD 患者的生命，但透析人群的心血管发病率和死亡率仍然极高。肾病患者罹患心脏病的倾向与多种因素有关，包括交感神经紧张、氧化应激增加和广泛的动脉钙化。为了研究 CKD/ESRD 心脏病的发病机制，我们假设肾脏的内分泌功能尚未完全了解，该器官分泌调节心脏功能的蛋白质，并且可以使用分子方法和遗传数据库分析相结合来识别这些蛋白质。这项努力导致了肾酶的发现，这是一种在肾脏和心脏中表达的新型 FAD 依赖性胺氧化酶。它分泌到血液中，并降解循环中的儿茶酚胺。肾酶给药可以降低血压，还可以预防急性心肌缺血。血液水平与肾功能呈正相关，CKD 和 ESRD 患者的肾酶水平较低。肾酶途径的分子细节开始显现，我们发现儿茶酚胺调节肾酶基因表达、分泌和酶激活。我们假设肾酶在调节儿茶酚胺水平和交感神经活动中发挥关键作用，肾脏疾病中肾酶缺乏会导致交感神经张力增强、高血压和心血管风险增加。在这些发现和总体假设的背景下，我们建议检查儿茶酚胺和/或血压如何调节体内血液肾酶活性。我们将研究肾酶敲除小鼠介导高血压的机制。我们将使用转基因动物来确定肾脏对肾酶途径的具体贡献。这些研究将显着增强我们对肾酶途径的理解，并将开始阐明肾酶在高血压和与肾脏疾病相关的心血管并发症的发病机制中的作用。公共卫生相关性：两千万美国人患有慢性肾病，并且患致命和非致命心血管并发症的风险明显更高。该患者群体中心脏病的发病机制尚不清楚。肾病患者缺乏肾酶，肾酶是一种新发现的激素，在肾脏中产生，在血液中分泌，调节血压和心脏功能。肾酶本身或肾酶途径的成分可能为肾病患者提供有价值的治疗选择。