Adenosine Receptors in the Kidney

肾脏中的腺苷受体

基本信息

批准号：
8461930
负责人：
William J Welch
金额：
$ 32.62万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8461930
关键词：
Address Adenosine Affect Agonist American Angiotensin II Blood Pressure Blood Vessels Body Fluids Cardiovascular Diseases Cells Chronic Complex DOCA Defect Dependency Development Diuresis Dose Equilibrium Feedback Fluid Balance Goals Hand Harvest Homeostasis Hypertension In Vitro Infusion procedures Kidney Knockout Mice Knowledge Lead Link Liquid substance Maintenance Measurement Measures Mediating Mediator of activation protein Methods Micropuncture Modeling Morbidity - disease rate Mus Nephrons Peripheral Peripheral Resistance Play Prevention Purinergic P1 Receptors Regulation Renal function Risk Factors Role Site Sodium Chloride Staging System Techniques Testing Tissues Tubular formation Vascular resistance Wild Type Mouse arteriole blood pressure regulation constriction design in vivo kidney vascular structure mortality novel novel strategies prevent receptor research study salt balance salt intake salt sensitive solute uptake vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Hypertension is the major risk factor for cardiovascular diseases and affects over 70 million Americans. The kidney sets the long-term level of blood pressure by regulation of body fluid volume and ultimately peripheral resistance. Novel strategies to redirect the inappropriate increases in renal vascular resistance and tubular reabsorption address the problem of sustained hypertension. Adenosine is a major regulator of renal control of fluid balance and renal vascular resistance, acting on specific receptors in the proximal tubule and in the afferent arteriole. These two sites of action provide novel and sensitive regulation of fluid balance and have been targeted to manage fluid volume. Adenosine, type 1 and type 2 receptors (A1-AR, A2- AR) have opposing actions in both tissues. Activation of A1-AR constricts the afferent arteriole and promotes Na+ uptake in the proximal tubule. Activation of A2-AR dilates the afferent arteriole and inhibits Na+ uptake in the proximal tubule. Therefore the balance of these actions plays an important role in renal function, but is currently poorly understood. This project will explore the precise roles of each receptor in the uptake of proximal tubule Na+ and fluid and on the setting of renal vascular resistance mediated by tubuloglomerular feedback during two distinct models of hypertension in A1-AR deficient mice. Specific Aim one will test the hypothesis that adenosine-1 receptors in the proximal tubule promote Na+ and volume retention during salt- sensitive hypertension and that adenosine-2 receptors modulate that influence. Proximal tubule reabsorption will be measured by renal microperfusion and recollection techniques and correlated to blood pressure. Specific Aim two will test the hypothesis that adenosine-1 receptors in the afferent arteriole and in the proximal tubule enhances blood pressure increase during angiotensin II-induced hypertension. The role of adenosine-2 receptors as modulators of these effects will also be tested. Proximal tubule reabsorption and tubuloglomerular feedback, measured by renal micropuncture techniques, will be assessed during the early and late stages of hypertension after chronic angiotensin II infusion. In addition, vascular reactivity of afferent arterioles will be contrasted between these two models. Results from these studies will advance our knowledge of adenosine control of renal-dependent blood pressure regulation and identify new targets for therapy.

描述（由申请人提供）：高血压是心血管疾病的主要危险因素，影响着超过 7000 万美国人。肾脏通过调节体液量并最终调节外周阻力来设定血压的长期水平。重新定向肾血管阻力和肾小管重吸收的不适当增加的新策略解决了持续高血压的问题。腺苷是肾脏控制液体平衡和肾血管阻力的主要调节剂，作用于近端小管和传入小动脉中的特定受体。这两个作用位点提供了新颖且灵敏的体液平衡调节，并已针对管理体液量进行了控制。腺苷、1 型和 2 型受体（A1-AR、A2-AR）在两种组织中具有相反的作用。 A1-AR 的激活会收缩传入小动脉并促进近端小管中 Na+ 的摄取。 A2-AR 的激活会扩张传入小动脉并抑制近端小管中 Na+ 的摄取。因此，这些作用的平衡在肾功能中起着重要作用，但目前人们对此知之甚少。该项目将探讨在 A1-AR 缺陷小鼠的两种不同高血压模型中，每种受体在近端肾小管 Na+ 和液体的摄取以及肾小管肾小球反馈介导的肾血管阻力设置中的精确作用。具体目标一将检验以下假设：近曲小管中的腺苷 1 受体在盐敏感性高血压期间促进 Na+ 和容量潴留，而腺苷 2 受体调节这种影响。近端小管重吸收将通过肾微灌注和回忆技术进行测量，并与血压相关。具体目标二将检验以下假设：传入小动脉和近端小管中的腺苷 1 受体会在血管紧张素 II 诱导的高血压期间增强血压升高。腺苷 2 受体作为这些效应调节剂的作用也将得到测试。通过肾微穿刺技术测量的近端小管重吸收和肾小球反馈，将在慢性血管紧张素 II 输注后的高血压早期和晚期阶段进行评估。此外，传入小动脉的血管反应性将在这两个模型之间进行对比。这些研究的结果将增进我们对腺苷控制肾依赖性血压调节的认识，并确定新的治疗靶点。