ADENOSINE RECEPTORS IN THE KIDNEY

描述（由申请人提供）：腺苷调节由4种不同受体介导的几种生理系统：A1、A2 a、A2 b和A3。A1受体（A1-AR）在传入小动脉（AA）中的激活增加AA阻力并降低肾小球滤过率（GFR）。肾单位上皮细胞中的A1-AR介导钠和液体重吸收，并参与正常的稳态功能，但其在肾单位功能中的作用知之甚少。这项研究表明，A1-ARs介导的一个重要的肾内调节系统的近端小管（PT），肾小球肾小管平衡（GTB）。假设PT中局部产生的腺苷通过激活A1-AR响应液体输送的变化来调节液体和电解质重吸收，从而介导GTB。具体目标之一是评估PT中A1-AR表达对各种盐摄入和血管紧张素II输注的响应的调节。还将测量钠氢交换器3（NHE 3）（PT上皮细胞中的主要Na进入机制）和其他相关蛋白的表达，并将其与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的试剂直接微灌注PT来测量GTB。此外，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/液体重吸收之间联系的可能介质的作用。这些包括NHE 3、磷酸激酶C、G蛋白和其他。将评价药物对PT功能而非整个肾功能的直接作用。这些研究结合肾脏微灌注和微穿刺与分子和药理学工具，以评估A1-AR在PT中的作用，应导致更好地了解腺苷在肾脏中的调节作用。这些研究是及时的，因为最近关于A1-AR拮抗剂的临床试验报告了利尿和尿钠排泄增加，同时保持GFR，与PT效应一致。

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.