Renal Mechanisms in Blood Pressure Control

血压控制中的肾脏机制

基本信息

批准号：
9304292
负责人：
Allen W Cowley
金额：
$ 191.07万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304292
关键词：
African American Animals Automobile Driving Back Biochemistry Blood Pressure Blood flow Cell membrane Computers Coupled Dahl Hypertensive Rats Development Diffuse Diffusion Disease Event Exhibits Feeds Fumarate Hydratase Fumaric acid Generic Drugs Genes Genetic Models Homeostasis Human Hydrogen Peroxide Hypertension Image Infiltration Injury Intake Kidney Kidney Diseases Lead Limb structure Maintenance Malignant - descriptor Malignant Hypertension Metabolism Microscopy Mitochondria Modeling Molecular Monitor NADPH Oxidase Nitric Oxide Organ Pathway interactions Perfusion Phase Physiological Play Process Production Rattus Research Resistance Role Signal Transduction Sodium Sodium Chloride Superoxides System T-Lymphocyte Techniques Testing Thick Tissues Transgenic Organisms Tubular formation blood pressure regulation cytokine design disease phenotype feeding fluorescence imaging fluorophore genome wide association study interstitial neutrophil cytosol factor 67K novel novel strategies null mutation overexpression pressure programs protein expression response salt intake salt sensitive salt sensitive hypertension tool vasoconstriction

项目摘要

The integrating theme and unifying hypothesis of this PPG centers on the concept that H202 production in the renal outer medulla (CM) plays a dominant role in the development of salt-sensitive hypertension. Studies in this PPG will use Dahl salt-sensitive (SS) rats to examine physiological mechanisms and molecular pathways underlying salt-sensitive hypertension; it does not focus on the generic aspects of this disease. This rat model recapitulates many aspects of human salt-sensitive hypertension and demonstrates disease phenotypes which are very similar to those observed in African Americans. Project 1 explores the role of the medullary thick ascending limb (mTAL) and tests the hypothesis that increased salt intake leads to greater mTAL NaCI delivery resulting in excess production of H202 in SS rats as amplified by a greater expression of the p67phox subunit of NADPH oxidase. It is proposed that this results in greater H202 diffusion into the interstitial space thereby constricting vasa recta and reducing medullary perfusion. Project 2 hypothesizes that the initials rise of arterial pressure following an increase in salt intake leads to the infiltration of T-cells in the kidney which exaggerates salt-sensitive hypertension and renal disease by increasing H202 and cytokines. The resulting T-lymphocyte infiltration into the kidney, we propose, is importanfiy influenced by Sh2b3, a gene recently identified by GWAS to be associated with human hypertension. Project 3 hypothesizes that a newly discovered pathway of H202 production related to cellular metabolism contributes importantly to the development and maintenance of hypertension in SS rats. Specifically, fumarase insufficiency in SS rats results in an increase of fumaric acid and glycolytic activity which stimulates H202 production and contributes to the salt-induced hypertension. These conceptually unique hypotheses combined with novel technological tools will advance our understanding of the molecular and physiological mechanisms underlying salt-sensitive hypertension that remain largely unclear. This highly integrated and collaborative program of three projects is supported by an Administrative Core A, the Biochemistry/Microscopy Core B, and Genetic Model Tracking and Monitoring Core C.

该PPG的综合主题和统一假设的基础是，H202在肾外髓质（CM）中产生的概念在盐敏感性高血压的发展中起主要作用。该PPG的研究将使用DAHL盐敏感（SS）大鼠检查生理机制和盐敏感性高血压下的分子途径。它不关注该疾病的通用方面。这种大鼠模型概括了人类盐敏感的高血压的许多方面，并证明了与非裔美国人观察到的疾病表型非常相似。项目1探讨了髓质厚升肢（MTAL）的作用，并检验以下假设：增加盐的摄入会导致更大的MTAL NACI递送，从而导致SS大鼠中H202的过量产生，从而通过更大的表达NADPHPHOX氧化酶的p67phox亚基表达。有人提出，这会导致H202扩散到间质空间中，从而限制了VASA直肠并减少髓样灌注。项目2假设盐摄入量增加后动脉压的缩写会导致肾脏中T细胞的浸润，从而通过增加H202和细胞因子来夸大盐敏感的高血压和肾脏疾病。我们认为，由SH2B3影响的肾脏的T淋巴细胞浸润对肾脏的影响很大，SH2B3最近被GWAS鉴定出与人类高血压有关的基因。项目3假设，与细胞代谢有关的新发现的H202产生途径对SS大鼠的高血压的发展和维持至关重要。具体而言，SS大鼠的富马酶不足会导致富马酸和糖酵解活性的增加，从而刺激H202产生并有助于盐引起的高血压。这些在概念上独特的假设与新颖的技术工具相结合，将促进我们对盐敏感高血压下的分子和生理机制的理解，这些高血压在很大程度上不清楚。这三个项目的高度集成和协作计划得到了行政核心A，生物化学/显微镜核心B以及遗传模型跟踪和监视CoreC的支持。