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

• 批准号: 7841255
• 负责人: Ningjun Li
• 金额: $ 23.79万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841255
• 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; 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; 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; overexpression; pressure; programs; research study; response; salt intake; salt sensitive; sensor; transcription factor; urinary

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）：已证明肾髓质中含有高度丰富的 HIF 脯氨酰羟化酶结构域酶（PHD），这些酶可作为氧传感器，通过促进转录因子的降解来调节缺氧诱导因子-1a（HIF-1a）的水平。鉴于肾髓质中许多 HIF-1a 靶基因的产物，如一氧化氮合酶 (NOS)、环氧合酶-2 (COX-2) 和血红素加氧酶-1 (HO-1) 是重要的抗高血压因子，并对高盐摄入有反应，我们假设 PHD 对 HIF-1a 介导的基因激活的调节重要有助于肾脏适应高盐负荷，从而促进肾脏适应高盐负荷。 动脉血压的调节。为了检验这一假设，我们将确定对高盐摄入的慢性肾脏适应性反应是否与正常大鼠肾髓质中 PHD 活性的降低以及随后 HIF-1a 介导的基因转录的激活有关（目标 1）。我们将进一步确定盐负荷诱导的 HIF-1a PHD 调节的改变是否与肾小管离子转运活性相关，以及盐诱导的 PHD 活性和表达变化沿着肾单位发生在何处。我们还将确定刺激 PHD 活性和 PHD2 基因过度表达以阻断肾髓质中 HIF-1a 介导的基因表达是否会增加动脉血压的盐敏感性（目标 2）。最后，我们将检查肾髓质中 HIF-1a 介导的基因表达的 PHD 调节功能障碍是否会导致 Dahl 盐敏感性高血压大鼠的盐敏感性高血压，并探索该大鼠品系中 PHD 表达或活性缺陷的机制，重点关注局部氧化应激的可能作用（目标 3）。这些拟议研究的结果将确定介导肾髓质适应高盐摄入的重要分子机制，并为盐敏感性高血压的发病机制提供新的见解。相关性：高盐饮食会使肾脏中含有脯氨酰羟化酶结构域（PHD）的酶失活，从而增加一些保护基因和相关因子的表达，从而增加尿盐排泄。如果这种酶不能正常工作，过量吃的盐就无法被清除，就会出现盐敏感型高血压。这一机制的阐明最终将提出治疗高血压的新疗法。