Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure

肾髓质HIF脯氨酰羟化酶与血压盐敏感性

基本信息

批准号：
7481007
负责人：
Ningjun Li
金额：
$ 33.53万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-07 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481007
关键词：
Angiotensin II Animal Model Antihypertensive Agents Attenuated Blood Pressure Blood flow Carbon Monoxide Chronic Data Diet Eating Enzyme Inhibition Enzymes Excretory function Functional disorder Gene Activation Gene Expression Gene Targeting Genes Genetic Transcription High Blood Pressure Hypertension Hypoxia Hypoxia Inducible Factor Inbred Dahl Rats Ion Transport Kidney Mediating Modeling Molecular Natriuresis Nephrons Nitric Oxide Nitric Oxide Synthase Oxidative Stress Oxygen Pathogenesis Physiological Procollagen-Proline Dioxygenase Production Prostaglandins Protein Overexpression Rat Strains Rattus Rectum Regulation Renal function Research Personnel Right-On Role Sodium Sodium Chloride Sprague-Dawley Rats Testing Tubular formation Vasoconstrictor Agents Work base cyclooxygenase 2 enzyme activity heme oxygenase-1 insight kidney medulla pressure programs research study response salt intake salt sensitive sensor transcription factor urinary

项目摘要

DESCRIPTION (provided by applicant): HIF prolyl hydroxylase domain-containing enzymes (PHDs) have been shown highly abundant in the renal medulla, which serve as oxygen sensors to regulate Hypoxia-inducible factor-la (HIF-1a) levels by promoting the degradation of this transcription factor. Given that the products of many HIF-1 a target genes such as nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) in the renal medulla are important antihypertensive factors and respond to high salt intake, we hypothesize that PHD regulation of HIF-1 a mediated gene activation importantly contributes to renal adaptation to high salt loading and thereby to the regulation of arterial blood pressure. To test this hypothesis, we will determine whether chronic renal adaptive response to high salt intake is associated with decrease in PHD activity and consequent activation of HIF-1 a-mediated gene transcription in the renal medulla of normal rats (Aim 1). We will further determine whether salt loading-induced alterations of PHD regulation of HIF-1 a are associated with tubular ion transport activity and where the salt-induced changes in PHD activity and expression occur along the nephron. We will also determine whether stimulation of PHD activity and overexpression of PHD2 gene to block HIF-1 a mediated gene expression in the renal medulla increases the salt sensitivity of arterial blood pressure (Aim 2). Finally, we will examine whether dysfunction in PHD regulation of HIF-1 a-mediated gene expression in the renal medulla contributes to salt-sensitive hypertension in Dahl salt-sensitive hypertensive rats and to explore the mechanisms responsible for the deficiency of PHD expression or activity in this rat strain with a focus on the possible role of local oxidative stress (Aim 3). The results from these proposed studies will define an important molecular mechanism mediating renal medullary adaptation to high salt intake and provide new insights into the pathogenesis of salt-sensitive hypertension. Relevance: High salt diet inactivates an enzyme containing prolyl hydroxylase domains (PHDs) in the kidney, which increases the expression of some protective genes and related factors, and thereby increases urinary salt excretion. If this enzyme is not working properly, excessively eaten salt cannot be removed, and salt-sensitive high blood pressure occurs. Clarification of this mechanism will ultimately suggest new therapies for treatment of high blood pressure.

描述（由申请人提供）：HIF丙酰羟化酶结构域（PHDS）在肾脏髓质中已显示出高度丰富，该肾脏是通过促进该转录因子降解来调节低氧诱导因子LA（HIF-1A）水平的氧气传感器。 Given that the products of many HIF-1 a target genes such as nitric oxide synthase (NOS), cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) in the renal medulla are important antihypertensive factors and respond to high salt intake, we hypothesize that PHD regulation of HIF-1 a mediated gene activation importantly contributes to renal adaptation to high salt loading and thereby to the调节动脉血压。为了检验这一假设，我们将确定对高盐摄入量的慢性肾脏自适应反应是否与PHD活性的降低以及随之而来的HIF-1 A介导的基因转录在正常大鼠的肾脏髓质中的激活有关（AIM 1）。我们将进一步确定盐负荷诱导的HIF-1 A的PHD调节变化是否与管状离子转运活性以及盐诱导的PHD活性和表达发生在肾单位发生的情况下有关。我们还将确定刺激PHD活性和PHD2基因的过表达是否阻断HIF-1 A肾脏髓质中介导的基因表达会增加动脉血压的盐灵敏度（AIM 2）。最后，我们将检查肾脏髓质中HIF-1 A介导的基因表达的PHD调节功能障碍是否有助于DAHL盐敏感性高血压大鼠的盐敏感性高血压，并探索使该大鼠菌株缺乏局部氧化应激的作用（AIL 3）。这些提出的研究的结果将定义一种重要的分子机制，介导肾脏髓样适应高盐的摄入量，并为盐敏感性高血压的发病机理提供新的见解。相关性：高盐饮食会使肾脏中含有羟化酶域（PHD）的酶失活，从而增加了某些保护基因和相关因素的表达，从而增加了尿液的排泄。如果该酶无法正常工作，则无法去除过度食用的盐，并且会发生对盐敏感的高血压。澄清这种机制将最终提出用于治疗高血压的新疗法。