ADENOSINE RECEPTORS IN THE KIDNEY

肾脏中的腺苷受体

• 批准号: 7089466
• 负责人: William J Welch
• 金额: $ 25.45万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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/7089466
• 关键词: adenosine; angiotensin II; angiotensin receptor; arterioles; diuresis; glomerular filtration rate; kidney function; kidney pharmacology; laboratory rat; nutrition related tag; protein kinase C; purinergic receptor; renal tubular transport; salt intake; sodium hydrogen exchanger; vascular resistance; western blottings

DESCRIPTION (provided by applicant): 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 reabsorption 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 be 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.

描述（由申请人提供）：腺苷调节由 4 种不同受体介导的多种生理系统：A1、A2a、A2b 和 A3。传入小动脉 (AA) 中 A1 受体 (A1-AR) 的激活会增加 AA 阻力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，并与正常的稳态功能有关，但它们在肾单位功能中的作用尚不清楚。本研究提出 A1-AR 介导近端肾小管 (PT)、肾小球小管平衡 (GTB) 中重要的肾内调节系统。该假说认为，PT 局部产生的腺苷通过响应液体输送的变化而激活 A1-AR 来调节液体和电解质的重吸收，从而介导 GTB。具体目标一是评估 PT 中 A1-AR 表达的调节，以响应不同的盐摄入量和血管紧张素 II 输注。钠氢交换器 3 (NHE3)（PT 上皮细胞中主要的 Na 进入机制）和其他相关蛋白的表达也将被测量，并与 A1-AR 表达的变化相关联。在第二个目标中，将通过用抑制和激活 A1-AR 的药物直接微灌注 PT 来测量 GTB。此外，还将测量 GTB 对盐摄入量变化、长期血管紧张素 II 治疗和血管紧张素受体急性抑制的功能反应。将评估 A1-AR 和 Na/液体重吸收之间的联系的可能介体的作用。其中包括 NHE3、磷酸激酶 C、G 蛋白等。将评估药物对 PT 功能而非整个肾功能的直接作用。这些研究将肾脏微灌注和微穿刺与分子和药理学工具相结合，以评估 A1-AR 在 PT 中的作用，应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利尿和尿钠排泄，同时保持 GFR，与 PT 效果一致。