Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure

描述（由申请人提供）：已显示含HIF脯氨酰羟化酶结构域的酶（PHD）在肾髓质中高度丰富，其作为氧传感器通过促进该转录因子的降解来调节缺氧诱导因子-la（HIF-1a）水平。考虑到许多HIF-1 α靶基因的产物如肾髓质中的一氧化氮合酶（NOS）、环氧合酶-2（考克斯-2）和血红素加氧酶-1（HO-1）是重要的抗高血压因子并且响应于高盐摄入，我们假设PHD对HIF-1 α的调节1a介导的基因激活重要地有助于肾适应高盐负荷，从而调节动脉血压。为了验证这一假设，我们将确定慢性肾适应性反应高盐摄入是否与PHD活性的降低和随后的正常大鼠肾髓质中HIF-1 α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调节HIF-1 α的改变是否与肾小管离子转运活性相关，以及盐诱导的PHD活性和表达的变化沿着肾单位发生。我们还将确定刺激PHD活性和过表达PHD 2基因以阻断肾髓质中HIF-1 α介导的基因表达是否会增加动脉血压的盐敏感性（目的2）。最后，我们将研究是否在PHD调节HIF-1 α介导的基因表达在肾髓质功能障碍，有助于盐敏感性高血压Dahl盐敏感性高血压大鼠，并探讨机制负责缺乏PHD表达或活动在这只大鼠品系的重点是可能的作用，局部氧化应激（目的3）。这些研究的结果将确定一个重要的分子机制，介导肾髓质适应高盐摄入，并提供盐敏感性高血压的发病机制的新见解。相关性：高盐饮食使肾脏中含有脯氨酰羟化酶结构域（PHDs）的酶失活，这增加了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，过量摄入的盐就不能被清除，盐敏感性高血压就会发生。阐明这一机制将最终为治疗高血压提供新的治疗方法。

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.