Adenosine Receptors in the Kidney

肾脏中的腺苷受体

• 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
• 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

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长期血压水平。重新定向肾血管阻力和肾小管重吸收不适当增加的新策略解决了持续性高血压的问题。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而敏感的流体平衡调节，并被用于控制流体体积。腺苷，1型和2型受体（A1-AR, A2- AR）在两种组织中都有相反的作用。A1-AR的激活收缩传入小动脉，促进近端小管Na+的摄取。A2-AR的激活扩张传入小动脉，抑制近端小管Na+的摄取。因此，这些作用的平衡在肾功能中起着重要作用，但目前知之甚少。本项目将探讨在两种不同的A1-AR缺陷小鼠高血压模型中，每种受体在近端小管Na+和液体摄取以及小管-肾小球反馈介导的肾血管阻力设置中的确切作用。特异性目的一将检验近端小管中的腺苷-1受体在盐敏感性高血压期间促进Na+和体积保留，腺苷-2受体调节这种影响的假设。近端小管重吸收将通过肾微灌注和回忆技术测量，并与血压相关。特异性目的2将验证传入小动脉和近端小管中的腺苷-1受体在血管紧张素ii诱导的高血压期间提高血压升高的假设。腺苷-2受体作为这些效应的调节剂的作用也将被测试。通过肾微穿刺技术测量近端小管重吸收和小管肾小球反馈，将在慢性血管紧张素II输注后高血压的早期和晚期进行评估。此外，传入小动脉的血管反应性将在这两种模型之间进行对比。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。