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中文摘要
翻译
腺苷通过4种不同的受体A1、A2a、A2b调节多种生理系统 和A3。传入小动脉A1受体(A1-AR)的激活增加AA抵抗 并降低肾小球滤过率(GFR)。肾单位上皮细胞中的A1-ARs介导 钠和液体重吸收,并与正常的体内平衡功能有关,但它们在 肾单位功能知之甚少。本研究认为,A1-ARs介导了一个重要的 近端肾小管肾内调节系统(PT)、肾小管平衡(GTB)。这个 假说是在甲状旁腺局部产生的腺苷调节液体和电解质的再利用。 通过激活A1-AR以响应液体输送的变化,从而调节GTB。 具体目的一将评估A1-AR在甲状旁腺皮质中表达的调节 各种盐的摄入和血管紧张素II的输注。钠氢交换器的表达 3(NHE3),甲状旁腺上皮细胞的主要钠进入机制,以及其他相关蛋白将 也可被测量并与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-ARs的试剂直接对PT进行微灌流来测量。在……里面 此外,GTB对盐摄入量变化的功能反应,长期应用血管紧张素II治疗 并将测量血管紧张素受体的急性抑制。可能的调解人的角色 将评估A1-AR和钠/液体重吸收之间的联系。其中包括,NHE3, 磷酸激酶C、G蛋白等。药物对PT功能的直接作用,而不是 将对全肾功能进行评估。这些研究结合了肾脏微灌注和 应用分子和药理学手段评价A1-AR在甲状旁腺功能障碍中的作用 应该有助于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增加了利尿和 在保持肾小球滤过率的同时排钠,与PT效果一致。
英文摘要
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.
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Adenosine Receptors in the Kidney
  • 批准号:
    8235205
  • 项目类别:
  • 资助金额:
    $33.71万
  • 财政年份:
    2012
  • 负责人:
    William J Welch
  • 依托单位:
Adenosine Receptors in the Kidney
  • 批准号:
    8461930
  • 项目类别:
  • 资助金额:
    $32.62万
  • 财政年份:
    2012
  • 负责人:
    William J Welch
  • 依托单位:
Adenosine Receptors in the Kidney
  • 批准号:
    8702149
  • 项目类别:
  • 资助金额:
    $33.82万
  • 财政年份:
    2012
  • 负责人:
    William J Welch
  • 依托单位:
ANIMAL CORE
  • 批准号:
    8148033
  • 项目类别:
  • 资助金额:
    $32.75万
  • 财政年份:
    2010
  • 负责人:
    William J Welch
  • 依托单位:
国内基金
海外基金
基于ADK/Adenosine调控DNA甲基化探讨“利湿化瘀通络”法对2型糖尿病肾病足细胞裂孔膜损伤的干预机制研究
  • 批准号:
    82074359
  • 项目类别:
    面上项目
  • 资助金额:
    55.0万元
  • 批准年份:
    2020
  • 负责人:
    安晓飞
  • 依托单位:
细胞外腺苷(Adenosine)作为干细胞旁分泌因子的生物学鉴定和功能分析
Adenosine诱导A1/A2AR稳态失衡启动慢性低灌注白质炎性损伤及其机制