Adenosine Receptors in the Kidney

肾脏中的腺苷受体

• 批准号: 8235205
• 负责人: William J Welch
• 金额: $ 33.71万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/8235205
• 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

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. PUBLIC HEALTH RELEVANCE: Hypertension is the leading cause of cardiovascular disease, affecting over 70 million Americans. Novel treatments for the prevention of the development of hypertension would have great benefits. This study will explore an under-appreciated system in the kidney that regulates fluid and salt balance, and try to link it to blood pressure control. The designed experiments will provide new information about the pro-hypertensive role of adenosine receptors, which has been previously unrecognized. This study may lead to the development of novel agents to treat specific forms of hypertension.

描述（由申请人提供）：高血压是心血管疾病的主要危险因素，影响超过7000万美国人。肾脏通过调节体液容量和最终外周阻力来设定血压的长期水平。新的策略，以重新定向肾血管阻力和肾小管重吸收的不适当增加的问题，持续高血压。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异性受体。这两个作用部位提供了对液体平衡的新颖和灵敏的调节，并且已经被靶向用于管理液体体积。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的激活收缩传入小动脉并促进近端小管中的Na+摄取。A2-AR的激活使传入小动脉扩张并抑制近端小管中的Na+摄取。因此，这些作用的平衡在肾功能中起着重要作用，但目前知之甚少。本项目将探讨每种受体在近端小管Na+和液体摄取中的确切作用，以及在A1-AR缺陷小鼠的两种不同高血压模型中由肾小管肾小球反馈介导的肾血管阻力的设置。具体目标一将检验这样的假设，即在盐敏感性高血压期间，近端小管中的腺苷-1受体促进Na+和容量保留，并且腺苷-2受体调节该影响。近端小管重吸收将通过肾微灌注和再收集技术测量，并与血压相关。具体目标二将检验这一假设，即在血管紧张素II诱导的高血压过程中，传入小动脉和近端小管中的腺苷-1受体增强血压升高。腺苷-2受体作为这些作用的调节剂的作用也将进行测试。将在慢性血管紧张素II输注后的高血压早期和晚期评估通过肾微穿刺技术测量的近端小管重吸收和肾小球反馈。此外，将对比这两种模型之间的传入小动脉的血管反应性。这些研究的结果将促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。 公共卫生相关性：高血压是心血管疾病的主要原因，影响超过7000万美国人。预防高血压发展的新疗法将有很大益处。这项研究将探索肾脏中一个被低估的调节水盐平衡的系统，并试图将其与血压控制联系起来。设计的实验将提供有关腺苷受体的促高血压作用的新信息，这是以前未被认识到的。这项研究可能会导致开发新的药物来治疗特定形式的高血压。