Mechanisms of Salt-Sensitive Hypertension and Hypertensive Nephrosclerosis

描述(由申请人提供)： 项目摘要/摘要 高血压和高血压肾病是一种常见的疾病，共同造成了极高的疾病负担。该实验室的研究表明，食盐摄入量在终末器官损伤中起着关键作用，并提出了一种新的范式，涉及内皮在转化生长因子-1(TGF-β1)的产生中的中心作用，以响应盐摄入量的变化，以及内皮来源的NO在血管壁和肾小球中产生的转化生长因子-β1的调节作用。这些发现强调了这样一个概念，即内皮的可塑性在维持血管张力和肾功能方面发挥着不可或缺的作用，以应对饮食盐摄入量的变化。这一更新应用的工作假设是，饮食盐摄入量调节内皮细胞信号事件，内皮细胞参与产生包括转化生长因子-1和一氧化氮在内的生物活性分子，而一氧化氮的产生受损有助于盐敏感型高血压患者转化生长因子-1的活性。第一个具体目标将确定食盐上调转化生长因子-1的信号转导事件，并将重点放在蛋白激酶C(PKC)和富含脯氨酸的酪氨酸激酶2(PYK2，也称为RAFTK、CAK-和CADTK)上。目的2将确定盐诱导转化生长因子β1产生的机制和NO抑制内皮细胞产生转化生长因子β1的机制。目的3将确定参与NO产生的内皮亚型一氧化氮合酶(NOS3)在盐摄入量增加时的翻译后修饰以及NOS3功能受损的机制。长期目标是确定盐摄入量对血管和肾脏内皮细胞功能的功能适应和后果。通过确定内皮细胞中的信号转导途径以及NO和转化生长因子β1之间的相互关系，这一应用将为高血压和盐摄入改变引起的小动脉和肾脏损伤提供新的见解，并可能提供新的方法来抑制转化生长因子β1的功能，而不依赖于肾素-血管紧张素-醛固酮轴的抑制。 项目叙事 长期目标是确定盐摄入量对血管和肾脏内皮细胞功能的功能适应和后果。通过确定内皮细胞中的信号转导途径以及NO和转化生长因子β1之间的相互关系，这一应用将为高血压和盐摄入改变引起的小动脉和肾脏损伤提供新的见解，并可能提供新的方法来抑制转化生长因子β1的功能，而不依赖于肾素-血管紧张素-醛固酮轴的抑制。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Hypertension and hypertensive renal disease are a common conditions that together create an extremely high disease burden. Work from this laboratory showed that dietary salt intake plays a key role in end-organ injury and suggested a new paradigm involving a central role of the endothelium in production of transforming growth factor-¿1 (TGF-¿1) in response to changes in salt intake and a modulating role for endothelium-derived NO in TGF-¿1 production in the vessel wall and glomerulus. The findings emphasized the concept that plasticity of the endothelium plays an integral role in maintaining vascular tone and renal function in response to changes in dietary salt intake. The working hypotheses of this renewal application are that dietary salt intake modulates endothelial cell signaling events involved in the production of bioactive molecules, including TGF- ¿1 and NO, and that impaired NO production facilitates TGF- ¿1activity in salt-sensitive hypertension. The first specific aim will determine the signal transduction events involved in the up-regulation of TGF- ¿1 by dietary salt and will focus on protein kinase C (PKC) and proline-rich tyrosine kinase 2 (Pyk2, also known as RAFTK, CAK- ¿ and CADTK). Aim 2 will determine the mechanism of salt-induced active TGF- ¿1 production and the mechanism by which NO inhibits endothelial cell production of TGF- ¿1. Aim 3 will define the post-translational modifications of the endothelial isoform of nitric oxide synthase (NOS3) involved in NO production in response to increased salt intake and the mechanism of impaired NOS3 function in S rats. The long-term goal is to determine the functional adaptation and consequences of salt intake on endothelial cell function in the vasculature and the kidney. By defining the signal transduction pathway in endothelial cells and the interrelationship between NO and TGF- ¿1, this application will provide novel insights into events that initiate injury in the arterioles and kidney associated with hypertension and changes in salt intake and potentially provide new approaches to inhibition of TGF- ¿1 function independently of inhibition of the renin-angiotensin-aldosterone axis. PROJECT NARRATIVE The long-term goal is to determine the functional adaptation and consequences of salt intake on endothelial cell function in the vasculature and the kidney. By defining the signal transduction pathway in endothelial cells and the inter-relationship between NO and TGF- ¿1, this application will provide novel insights into events that initiate injury in the arterioles and kidney associated with hypertension and changes in salt intake and potentially provide new approaches to inhibition of TGF- ¿1 function independently of inhibition of the renin-angiotensin-aldosterone axis.