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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的整合主题和统一假设围绕着H202在肾外髓质（CM）的产生在盐敏感性高血压的发展中起主导作用的概念。