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Renal Medullary HIF Prolyl Hydroxylases and Salt Sensitivity of Blood Pressure

肾髓质 HIF 脯氨酰羟化酶与血压的盐敏感性

基本信息

批准号：
9094599
负责人：
Ningjun Li
金额：
$ 38.13万
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 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9094599
关键词：
Aftercare Antihypertensive Agents Blood Pressure CMV promoter Chronic Dactinomycin Data Defect Development Eating Endogenous Factors Enzymes Equilibrium Excretory function Functional disorder Funding Genes Genetic Transcription Health Hypertension Hypoxia Inducible Factor Impairment In Vitro Kidney Luciferases Measures Mediating Mediator of activation protein Messenger RNA MicroRNAs Modeling Molecular Natriuresis Nitric Oxide Synthase Pathogenesis Pathway interactions Plasmids Procollagen-Proline Dioxygenase Production Protein Isoforms Proteins Rattus Regulation Reporter Sodium Sodium Chloride Sodium-Restricted Diet System Testing Transfection Transgenes Untranslated Regions Urine Work bHLH-PAS factor HLF base cyclooxygenase 2 heme oxygenase-1 high salt diet in vivo inhibitor/antagonist insight kidney medulla mRNA Decay mRNA Transcript Degradation normotensive novel novel therapeutics overexpression pressure prevent response salt intake salt sensitive salt sensitive hypertension vector

项目摘要

DESCRIPTION (provided by applicant): Hypoxia inducible factor (HIF)-1alpha is a transcriptional factor that is highly expressed in the renal medulla and regulates many anti-hypertensive genes, such as heme oxygenase-1, cyclooxygenase-2 and nitric oxide synthase-2, in this kidney region. Prolyl hydroxylase domain-containing protein-2 (PHD2) is the major enzyme to promote the degradation of HIF-1alpha in the renal medulla. In the last funding period, we proved that high salt intake reduced PHD2 mRNA levels in the renal medulla, which consequently induced HIF-1alpha-mediated activation of anti-hypertensive genes. This PHD2/HIF-1alpha-mediated molecular adaptation in the renal medulla is important for the kidneys to remove extra Na+ loading and maintain normal blood pressure under high salt intake. The question remains: how does high salt intake reduce PHD2 mRNA? Our preliminary studies showed that high salt diet enhanced the degradation of PHD2 mRNA in the renal medulla and that microRNA miR-429 was probably the upstream mediator for high salt-induced enhancement of PHD2 mRNA decay: 1) among the microRNAs that target PHD2 mRNA, miR-429 levels were increased by high salt intake in the renal medulla; 2) miR-429 was shown to target PHD2 mRNA 3'-UTR; 3) miR-429 reduced PHD2 mRNA levels in vitro and in vivo. Moreover, miR-429 inhibitor blocked the high salt- induced decrease in PHD2 mRNA in the renal medulla and produced salt sensitive hypertension in normal rats. We also detected impairment in miR-429 in the renal medulla in Dahl salt-sensitive hypertensive (SS) rats. Based on these preliminary data, we hypothesize that miR-429 regulation of PHD2/HIF-1alpha-mediated activation of anti-hypertensive genes in the renal medulla contributes to renal salt adaptation and participates in the controls of renal Na+ handling and blood pressure. To test this hypothesis, we will first determine whether chronic renal adaptation to high salt intake is associated with an increase in miR-429, which decreases PHD2 levels and activates HIF-1alpha-mediated transcriptions of anti-hypertensive genes in the renal medulla in normal rats. We will then determine whether inhibition of miR-429 function to prevent PHD2 reduction and to diminish HIF-1alpha-mediated activation of anti-hypertensive genes in the renal medulla will blunt pressure natriuresis and impair renal Na+ handling, leading to salt sensitive hypertension in normal rats. Finally, we will determine whether salt-sensitive hypertension in Dahl SS rats is associated with the dysfunction in miR-429- mediated molecular adaptation related to PHD2/HIF-1alpha-pathway in the renal medulla and also investigate the mechanisms that cause the deficiency of renal medullary miR-429 in this hypertensive model. The proposed studies will reveal a novel molecular mechanism mediating renal adaptation to high salt intake and provide new insights into the pathogenesis of salt-sensitive hypertension.

描述（由申请人提供）：缺氧诱导因子（HIF）-1 α是一种转录因子，在肾髓质中高度表达，并调节该肾区域的许多抗高血压基因，如血红素加氧酶-1、环氧合酶-2和一氧化氮合酶-2。含脯氨酰羟化酶结构域蛋白-2（PHD 2）是促进肾髓质中HIF-1 α降解的主要酶。在上一个资助期，我们证明高盐摄入降低了肾髓质中PHD 2 mRNA水平，从而诱导HIF-1 α介导的抗高血压基因激活。这种PHD 2/HIF-1 α介导的肾髓质分子适应对于肾脏在高盐摄入下清除额外的Na+负荷和维持正常血压是重要的。问题仍然存在：高盐摄入如何减少PHD 2 mRNA？我们的初步研究表明，高盐饮食促进了肾髓质中PHD 2 mRNA的降解，而microRNA miR-429可能是高盐诱导的PHD 2 mRNA降解增强的上游介质：1）在靶向PHD 2 mRNA的microRNA中，高盐摄入增加了肾髓质中miR-429的水平; 2）miR-429显示靶向PHD 2 mRNA 3 '-UTR; 3）miR-429在体外和体内降低PHD 2 mRNA水平。此外，miR-429抑制剂阻断了高盐诱导的肾髓质中PHD 2 mRNA的减少，并在正常大鼠中产生盐敏感性高血压。我们还检测到Dahl盐敏感性高血压（SS）大鼠肾髓质中miR-429的损伤。基于这些初步数据，我们假设miR-429调节PHD 2/HIF-1 α介导的肾髓质中抗高血压基因的激活有助于肾盐适应，并参与肾Na+处理和血压的控制。为了验证这一假设，我们将首先确定慢性肾脏对高盐摄入的适应是否与miR-429的增加有关，miR-429降低了PHD 2水平并激活了正常大鼠肾髓质中HIF-1 α介导的抗高血压基因的转录。然后，我们将确定抑制miR-429功能以防止PHD 2减少并减少肾髓质中HIF-1 α介导的抗高血压基因的激活是否会减弱压力性尿钠排泄并损害肾Na+处理，从而导致正常大鼠的盐敏感性高血压。最后，我们将确定Dahl SS大鼠的盐敏感性高血压是否与肾脏髓质中与PHD 2/HIF-1 α通路相关的miR-429介导的分子适应功能障碍相关，并研究在该高血压模型中导致肾脏髓质miR-429缺乏的机制。这些研究将揭示一种新的介导肾脏适应高盐摄入的分子机制，并为盐敏感性高血压的发病机制提供新的见解。