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Intrarenal Mechanisms of Ghrelin in Obesity-Hypertension

生长素释放肽在肥胖-高血压中的肾内机制

基本信息

批准号：
9901519
负责人：
SHETAL H PADIA
金额：
$ 35.55万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-25 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901519
关键词：
Blood Pressure Blood Vessels Chronic Conscious Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Duct (organ) structure Ductal Epithelial Cell Embryo Epidemic Equilibrium Essential Hypertension Excretory function Foundations Gene Expression Gene Expression Regulation Glomerular Filtration Rate Goals High Fat Diet Hormones Human Hypertension In Vitro Infusion procedures Kidney Knowledge Liquid substance Measures Mediating Mediator of activation protein Metabolic Microdialysis Mission Modeling Molecular Natriuresis Obesity Pathogenesis Pathway interactions Perfusion Pharmacology Physiological Pituitary Gland Production Public Health RNA Rattus Regulation Renal Blood Flow Reporting Research Risk Role Signal Pathway Sodium Stomach System Techniques Telemetry Testing Time Tissues Tubular formation United States National Institutes of Health Weight Weight Gain autocrine epithelial Na+ channel ghrelin ghrelin receptor in vivo increased appetite interstitial knock-down knockout gene mortality new therapeutic target novel preservation pressure prevent receptor receptor expression receptor function response success treatment optimization

项目摘要

PROJECT SUMMARY Excess weight gain contributes up to 65% of the risk of primary hypertension, and the increase in blood pressure (BP) in response to high-fat diet (HFD) is preceded by significant reductions in renal sodium (Na+) excretory capacity. Normal Na+ excretion is then only achieved at the expense of elevated renal perfusion pressure. Over time, the kidneys reset to require an elevated BP in order to continue to excrete a normal Na+ load. The knowledge of novel pathways regulating renal Na+ flux is therefore crucial to our success in optimizing therapy for major public health conditions such as obesity- hypertension. Recently, we reported that (1) direct renal infusion of ghrelin, the most potent, appetite-stimulating hormone in the body, activates GRs in the collecting duct (CD) to increase cAMP and ENaC-dependent Na+ reabsorption in rats; (2) renal infusion of a GR antagonist alone (to elucidate the actions of endogenous ghrelin), induces a robust natriuresis, indicating that physiological levels of circulating ghrelin regulate Na+ reabsorption under normal conditions; and (3) in HFD, renal GR expression is increased, and pharmacological blockade of intrarenal GRs prevents HFD- induced hypertension in rats. While these data establish some basic information regarding intrarenal GR expression and function, nothing is known about intrarenal production of ghrelin and its signaling pathways (Aim 1) or the contribution of GR-mediated antinatriuresis to the pathogenesis of HFD-induced hypertension (Aim 2). In this application, we propose studies in vitro using CD cells & in vivo using a HFD model of obesity- hypertension to study the mechanisms of the renal ghrelin-GR system. To isolate the role of the renal GR in chronic responses, we have developed a small inhibitory RNA (siRNA), that when infused chronically into the kidney, specifically transfects & knocks down CD GRs, while preserving GR expression in the other tissues. The major advantage of this over gene knockout is that it permits reduction in the gene expression without dangers of embryonic lethality and with less risk of compensatory gene regulation. We will also measure molecules released into the renal interstitium in response to renal manipulations of GR expression in conscious rats utilizing a novel microdialysis technique which permits analysis of mediators closer to target receptors and less prone to circulatory degradation. Thus, the ability to move fluidly between in vitro molecular and in vivo functional responses specific to the GR is a major significant aspect of the approach.

项目摘要体重过度增加导致65%的原发性高血压风险，高脂饮食（HFD）引起的血压（BP）升高之前，肾钠（Na+）显著降低排泄能力正常的Na+排泄只能以增加肾脏灌注为代价压力随着时间的推移，肾脏重置为需要升高的血压，以继续排泄正常的Na+。即可.因此，了解调节肾脏钠离子通量的新途径对于我们的成功至关重要。优化治疗主要的公共卫生条件，如肥胖-高血压。最近，我们报道说， (1)胃饥饿素是人体内最有效的食欲刺激激素，直接向肾脏输注胃饥饿素，收集管（CD）增加cAMP和ENaC依赖的Na+重吸收;（2）肾内输注a 单独的GR拮抗剂（以阐明内源性生长激素释放肽的作用）诱导强烈的尿钠排泄，表明生理水平的循环ghrelin调节Na+重吸收在正常条件下;和（3）在 HFD时，肾GR表达增加，肾内GR的药物阻断可预防HFD。诱导大鼠高血压虽然这些数据建立了一些关于肾内GR的基本信息，表达和功能，对肾内生长激素释放肽的产生及其信号传导途径一无所知 (Aim 1）或GR介导的抗尿钠排泄对HFD诱导的高血压发病机制的贡献 (Aim 2）。在本申请中，我们提出了使用CD细胞的体外研究和使用HFD肥胖模型的体内研究- 目的：研究肾脏ghrelin-GR系统的作用机制。为了分离肾脏GR在我们已经开发出一种小的抑制性RNA（siRNA），当长期输注到肾脏，特别是抑制和敲低CD GR，同时保留GR在其他组织中的表达。与基因敲除相比，这种方法的主要优点是，它允许基因表达的减少，而不需要基因敲除。胚胎致死的危险和补偿性基因调控的风险较小。我们还将测量有意识的人中，响应于GR表达的肾脏操作而释放到肾髓质中的分子利用新的微透析技术的大鼠，该技术允许分析更接近靶受体的介质，更不易发生循环系统退化。因此，能够在体外分子和体内分子之间流体地移动， GR特有的功能反应是该方法的一个重要方面。