Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure

描述(申请人提供)：在肾髓质中发现了高度丰富的含HIF-羟基酶结构域的酶(PhD)，它们作为氧感受器，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-1α靶基因如一氧化氮合酶(NOS)、环氧合酶-2(COX-2)和血红素氧合酶-1(HO-1)的产物是重要的抗高血压因子，并对高盐摄入作出反应，我们推测PHD对HIF-1α介导的基因激活的调节在肾脏对高盐负荷的适应从而调节动脉血压方面起重要作用。为了验证这一假说，我们将确定肾脏对高盐摄入的慢性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引起的PHD对HIF-1α调节的改变是否与肾小管离子转运活性有关，以及盐诱导的PHD活性和表达的变化发生在沿肾单位的位置。我们还将确定刺激PHD活性和PHD2基因的过度表达以阻断肾髓质中HIF-1α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调节功能障碍是否有助于Dahl盐敏感型高血压大鼠的盐敏感型高血压，并探索导致该品系大鼠PHD表达或活性不足的机制，重点是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一个重要的分子机制，介导肾脏髓质对高盐摄入的适应，并为盐敏感型高血压的发病机制提供新的见解。相关：高盐饮食使肾脏中一种含有脯氨酸羟基酶结构域(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，过量摄入的盐就不能被清除，就会发生盐敏感型高血压。阐明这一机制最终将为高血压的治疗提供新的治疗方法。

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.