ADENOSINE RECEPTORS IN THE KIDNEY

腺苷通过4种不同的受体A1、A2 a、A2 b调节多种生理系统 和A3。传入小动脉（AA）中A1受体（A1-AR）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-ARs介导 钠和液体重吸收，并涉及正常的自我平衡功能，但他们的作用， 肾单位的功能知之甚少。这项研究表明，A1-ARs介导了一个重要的 近曲小管（PT）的肾内调节系统，肾小球小管平衡（GTB）。的 假设是PT中局部产生的腺苷调节液体和电解质的再吸收 通过激活A1-AR以响应液体输送的变化，从而介导GTB。 具体目标是评估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。钠氢交换器的表达式 3（NHE 3），PT上皮细胞中主要的Na进入机制，以及其他相关蛋白将 也可以测量并与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的试剂直接微灌注PT来测量。在 此外，GTB对盐摄入量变化、长期血管紧张素II治疗的功能反应 并测量血管紧张素受体的急性抑制。可能的调解人的作用 将评估A1-AR和Na/液体重吸收之间的联系。这些包括，NHE 3， 磷酸激酶C、G蛋白等。药物对PT功能的直接作用， 将评价整个肾功能。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，以评估A1-AR在PT中的作用 这将使我们更好地理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增加， 尿钠排泄，同时保持GFR，与PT效应一致。

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.