Renal Mechanisms in Blood Pressure Control

该PPG的整合主题和统一假设集中在肾外髓质（CM）中的H2 O2产生在盐敏感性高血压的发展中起主导作用的概念上。 本PPG研究将使用Dahl盐敏感（SS）大鼠来检查盐敏感性高血压的生理机制和分子途径;它不关注这种疾病的一般方面。该大鼠模型概括了人类盐敏感性高血压的许多方面，并证明了与非裔美国人中观察到的非常相似的疾病表型。项目1探索了髓质粗升支（mTAL）的作用，并测试了以下假设：增加的盐摄入导致更大的mTAL NaCl递送，导致SS大鼠中H2 O2的过量产生，如通过NADPH氧化酶的p67 phox亚基的更大表达所放大的。提出这导致更大的H2 O2扩散到间质空间中，从而收缩直血管并减少髓质灌注。项目2假设盐摄入增加后动脉压的初始升高导致T细胞在肾脏中的浸润，这通过增加H2 O2和细胞因子而加重盐敏感性高血压和肾病。由此产生的T淋巴细胞浸润到肾脏，我们提出，是importanfiy影响Sh 2b 3，基因最近确定的GWAS与人类高血压。项目3假设新发现的与细胞代谢相关的H2 O2产生途径对SS大鼠高血压的发展和维持有重要贡献。具体地，SS大鼠中的脱氢酶不足导致富马酸和糖酵解活性的增加，其刺激H2 O2产生并促成盐诱导的高血压。这些概念上独特的假设与新的技术工具相结合，将推进我们对盐敏感性高血压的分子和生理机制的理解，这些机制在很大程度上仍不清楚。这三个项目的高度集成和协作计划由行政核心A，生物化学/显微镜核心B和遗传模型跟踪和监测核心C支持。

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.