Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure

描述（由申请人提供）：HIF脯氨酰羟化酶结构域含酶（PHDs）在肾髓质中被证明是高度丰富的，它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-la （HIF-1a）的水平。鉴于肾髓质中许多HIF-1 a靶基因的产物，如一氧化氮合酶（NOS）、环氧化酶-2 （COX-2）和血红素加氧酶-1 （HO-1）是重要的降压因子，并对高盐摄入有反应，我们假设PHD调节HIF-1 a介导的基因激活对肾脏适应高盐负荷并进而调节动脉血压有重要作用。为了验证这一假设，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活性的降低和hif - 1a介导的基因转录的激活有关（目的1）。我们将进一步确定盐负荷诱导的PHD对hif - 1a调控的改变是否与小管离子运输活性有关，以及盐诱导的PHD活性和表达的变化发生在肾元的何处。我们还将确定刺激PHD活性和过度表达PHD2基因以阻断hif - 1a介导的肾髓质基因表达是否会增加动脉血压的盐敏感性（目的2）。最后，我们将研究PHD对hif - 1a介导的肾髓质基因表达的调节功能障碍是否导致Dahl盐敏感性高血压大鼠的盐敏感性高血压，并探讨PHD表达或活性缺乏的机制，重点关注局部氧化应激的可能作用（目的3）。这些研究的结果将明确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：高盐饮食使肾脏中含有脯氨酸羟化酶结构域（PHDs）的酶失活，从而增加一些保护性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，过量食用的盐就不能清除，就会发生盐敏感性高血压。澄清这一机制将最终为治疗高血压提供新的疗法。

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.