ADENOSINE RECEPTORS IN THE KIDNEY

肾脏中的腺苷受体

基本信息

批准号：
7536288
负责人：
William J Welch
金额：
$ 1.94万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7536288
关键词：
Acute Adenosine Affinity Agonist Angiotensin II Angiotensin Receptor Angiotensins Binding Clinical Research Clinical Trials Data Diuresis Drug effect disorder Effectiveness Electrolytes Epithelial Cells Equilibrium GTP-Binding Proteins Glomerular Filtration Rate Individual Infusion procedures Kidney Lead Link Liquid substance Measurement Measures Mediating Mediation Mediator of activation protein Membrane Messenger RNA Methods Micropuncture Molecular Natriuresis Nephrons Pathway interactions Pharmaceutical Preparations Physiological Polymerase Chain Reaction Process Proteins Proximal Kidney Tubules Purinergic P1 Receptors Rate Rattus Regulation Renal function Reporting Research Personnel Resistance Role Series Signal Transduction Signaling Protein Small Interfering RNA Sodium Sodium Chloride Sodium-Hydrogen Antiporter System Testing Time Tubular formation activator 1 protein arteriole brush border membrane design in vivo programs radioligand receptor receptor density research study response salt intake sodium-hydrogen exchanger 3 tool

项目摘要

Adenosine regulates several physiological systems mediated by 4 distinct receptors: A1, A2a, A2b and A3. Activation of A1 receptors (A1-AR) in the afferent arterioles (AA) increases AA resistance and reduces the glomerular filtration rate (GFR). A1-ARs in epithelial cells of the nephron mediate sodium and fluid reabsorption and are implicated in normal homeostatic function, yet their role in nephron function is poorly understood. This study proposes that A1-ARs mediate an important intrarenal regulatory system in the proximal tubule (PT), glomerulotubular balance (GTB). The hypothesis is that adenosine produced locally in the PT regulates fluid and electrolyte reasborption through activation of A1-AR in response to changes in fluid delivery and thereby mediates GTB. Specific aim one will evaluate the regulation of the expression of A1-AR in the PT in response to various salt intakes and to angiotensin II infusions. Expression of the sodium hydrogen exchanger 3 (NHE3), the major Na entry mechanism in the epithelial cells of PT, and other related proteins will also be measured and correlated to changes in A1-AR expression. In the second aim, GTB will measured by direct microperfusion of the PT with agents that inhibit and activate A1-ARs. In addition, the GTB functional responses to changes in salt intake, long term angiotensin II treatment and acute inhibition of angiotensin receptors will be measured. The roles of possible mediators of the link between A1-AR and Na/fluid reabsorption will be assessed. These include, NHE3, phosphokinase C, G protein and others. The direct actions of drugs, on PT function rather than whole kidney function will be evaluated. These studies combining renal microperfusion and micropuncture with molecular and pharmacological tools to evaluate the role of A1-AR in the PT should lead to greater understanding of the regulatory role of adenosine in the kidney. These studies are timely, since recent clinical trials on A1-AR antagonists report increased diuresis and natriuresis while preserving GFR, consistent with a PT effect.

腺苷调节由 4 种不同受体介导的多个生理系统：A1、A2a、A2b 和A3。传入小动脉 (AA) 中 A1 受体 (A1-AR) 的激活会增加 AA 抵抗并降低肾小球滤过率（GFR）。肾单位上皮细胞中的 A1-AR 介导钠和液体的重吸收，与正常的稳态功能有关，但它们的作用对肾单位功能知之甚少。这项研究提出 A1-AR 介导了一个重要的肾内调节系统位于近端小管（PT）、肾小球小管平衡（GTB）。这假设是 PT 局部产生的腺苷调节液体和电解质重吸收通过响应液体输送的变化而激活 A1-AR，从而介导 GTB。具体目标一将评估 PT 中 A1-AR 表达的调节，以响应各种盐摄入量和血管紧张素 II 输注。钠氢交换剂的表达 3 (NHE3) 是 PT 上皮细胞中主要的 Na 进入机制，其他相关蛋白将也可测量并与 A1-AR 表达的变化相关。在第二个目标中，GTB 将通过用抑制和激活 A1-AR 的药物直接微灌注 PT 来测量。在此外，GTB 对盐摄入量变化的功能反应、长期血管紧张素 II 治疗并测量血管紧张素受体的急性抑制。可能的调解者的作用将评估 A1-AR 和 Na/液体重吸收之间的联系。这些包括，NHE3，磷酸激酶C、G蛋白等。药物对 PT 功能的直接作用而不是将评估整个肾功能。这些研究结合了肾脏微灌注和使用分子和药理学工具进行微穿刺评估 A1-AR 在 PT 中的作用应该有助于更好地了解腺苷在肾脏中的调节作用。这些研究是及时的，因为最近 A1-AR 拮抗剂的临床试验报告增加了利尿作用尿钠排泄同时保留 GFR，与 PT 效应一致。