Mechanisms of Salt-Sensitive Hypertension and Hypertensive Nephrosclerosis

描述（由申请人提供）： 项目总结/摘要 高血压和高血压肾病是共同造成极高疾病负担的常见病症。该实验室的工作表明，饮食中的盐摄入量在终末器官损伤中起着关键作用，并提出了一个新的范例，涉及内皮细胞在转化生长因子1（TGF-1）的产生中的核心作用，以响应盐摄入量的变化，以及内皮源性NO在血管壁和肾小球中TGF-1的产生中的调节作用。研究结果强调了这样一个概念，即内皮细胞的可塑性在维持血管张力和肾功能中起着不可或缺的作用，以应对饮食中盐摄入量的变化。这项更新申请的工作假设是，饮食中的盐摄入量调节内皮细胞信号传导事件，参与生物活性分子的产生，包括TGF-β 1和NO，并且在盐敏感性高血压中，受损的NO产生促进TGF-β 1活性。第一个具体目标将确定膳食盐上调TGF-β 1所涉及的信号转导事件，并将重点关注蛋白激酶C（PKC）和富含脯氨酸的酪氨酸激酶2（Pyk 2，也称为RAFTK，CAK-β和CADTK）。目的2将确定盐诱导的活性TGF-β 1产生的机制和NO抑制内皮细胞产生TGF-β 1的机制。目的3将确定参与NO生成的内皮型一氧化氮合酶（NOS 3）的翻译后修饰，以响应增加盐摄入和受损的NOS 3功能在S大鼠的机制。长期目标是确定盐摄入对血管系统和肾脏内皮细胞功能的功能适应和后果。通过定义内皮细胞中的信号转导途径以及NO和TGF-β 1之间的相互关系，本申请将提供对引发与高血压和盐摄入量变化相关的小动脉和肾脏损伤的事件的新见解，并可能提供独立于抑制肾素-血管紧张素-醛固酮轴的TGF-β 1功能抑制的新方法。 项目叙述 长期目标是确定盐摄入对血管系统和肾脏内皮细胞功能的功能适应和后果。通过定义内皮细胞中的信号转导途径以及NO和TGF-β 1之间的相互关系，本申请将提供对引发与高血压和盐摄入量变化相关的小动脉和肾脏损伤的事件的新见解，并可能提供独立于抑制肾素-血管紧张素-醛固酮轴的抑制TGF-β 1功能的新方法。

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.