AUTOCRINE/PARACRINE REGULATION OF RENAL MICROCIRCULATION

肾微循环的自分泌/旁分泌调节

• 批准号: 6649479
• 负责人: Oscar A. Carretero
• 金额: $ 7.35万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6649479
• 关键词: adenosine; adenosine triphosphate; angiotensin receptor; angiotensins; autocrine; calcium flux; glomerular filtration rate; hormone regulation /control mechanism; kidney circulation; laboratory rabbit; microcirculation; nitric oxide; nitric oxide synthase; paracrine; receptor expression; renal glomerulus; renal tubular transport; renal tubule; tissue /cell culture; transforming growth factors; vascular resistance; vasoactive agent; vasomotion

DESCRIPTION: (provided by applicant) In hypertension, regardless of its cause, renal vascular resistance increases, shifting the pressure natriuresis curve to the right. The afferent (Af-Art) and efferent arterioles (Ef-Art) account for most renal vascular resistance; they control glomerular filtration rate (GFR) and peritubular pressure, and consequently renal function. Af- and Ef-Art resistances are regulated by a balance between vasopressors (angiotensin, adenosine via the A1 receptor, reactive oxygen species) and vasodepressors (kinins, NO, adenosine via the A2 receptor). The Af-Art is also controlled by tubuloglomerular feedback (TGF). TGF operates via the macula densa, which senses Cl-, Na+ and/or solute load and sends a paracrine signal to the extraglomerular mesangial cells and/or the effectors of TGF, which are the Af-Art and Ef-Art. In addition to the TGF signal itself, the macula densa produces autocrine and paracrine factors that alter TGF either by acting on the macula densa or the Af- and Ef-Art, respectively. NO produced by macula densa neuronal NO synthase (nNOS), which attenuates TGF, is one such autacoid. We have evidence that the Ef-Art dilates rather than constricts during TGF and that the Ef-Art response to vasoactive hormones is modulated by paracrine factors produced by the glomerulus. Thus control of the renal microcirculation is complex and difficult to examine in vivo. For this reason, we propose to use a technique we developed that consists of in vitro perfusion of a microdissected Af- or Ef-Art and adherent tubular segment containing the macula densa. Using this preparation, we hypothesize that different and efferent resistance are regulated by autocrine and paracrine factors released from the glomerulus and the macula densa. Factors that promote dilatation include NO, prostaglandins (PGs) and 5,6 epoxyeicosatrienoic acid (EET). These are counterbalanced by factors that promote vasoconstriction including Ang II, thromboxane, 20- hydroxyeicosatetraenoic acid (HETE) and reactive oxygen species. Paracrine factors such as adenosine may have dilator or constrictor actions depending on whether A1 or A2 receptors are expressed on the target tissue. In Aim 1 we will test the hypothesis that when macula densa nNOS is increased, such as during low salt intake, NO released by the macula densa regulates basal Af-Art resistance even when the NaCl level in the macula densa is very low. In this situation, NO acts not only at the macula densa but also by diffusing from the macula densa to the Af-Art where it causes dilatation, thus preserving renal blood flow despite high renin. In Aim 2 we will test the hypothesis that by quenching NO released by macula densa nNOS, O2- determines a) the magnitude of TGF and b) whether NO acts only in an autocrine manner in the macula densa itself, or also in a paracrine mode by diffusing to the Af-Art and causing dilatation. In Aim 3 we will test the hypothesis that increased intracellular calcium in the macula densa acts as both a positive regulator by contributing to macula densa release of ATP and formation of adenosine in the interstitial space and a negative regulator of TGF by activating nNOS. In Aim 4 we will test the hypothesis that the glomerulus releases paracrine factors that control downstream Ef-Art resistance and consequently its own filtration pressure. In Aim 5 we will test the hypothesis that the mechanism of Ef-Art TGF is similar to Af-Art TGF, save that adenosine acts on the Ef-Art A2 receptor, causing dilatation. Thus reducing NO by inhibiting nNOS in the macula densa will potentiate Ef-Art TGF (greater dilatation).

描述：（由申请人提供） 在高血压中，无论其原因如何，肾血管阻力都会增加， 将压力尿钠曲线向右移动。传入（Af-Art） 和传出小动脉 (Ef-Art) 是肾血管阻力的主要来源； 它们控制肾小球滤过率（GFR）和肾小管周围压力，并且 因此肾功能。 Af- 和 Ef-Art 抗性由 血管加压剂之间的平衡（血管紧张素、通过 A1 受体的腺苷、 活性氧）和血管抑制剂（激肽、NO、通过 A2 的腺苷） 受体）。 Af-Art 还受肾小球反馈 (TGF) 控制。 TGF 通过密集黄斑发挥作用，感知 Cl-、Na+ 和/或溶质负荷 并向肾小球外系膜细胞和/或肾小球系膜细胞发送旁分泌信号 TGF 的效应器，即 Af-Art 和 Ef-Art。除了转化生长因子 信号本身，致密黄斑产生自分泌和旁分泌因子 通过作用于致密斑或 Af- 和 Ef-Art 来改变 TGF， 分别。 NO 由致密斑神经元 NO 合酶 (nNOS) 产生， 减弱 TGF，就是这样一种自体物质。我们有证据表明 Ef-Art 会扩张 而不是在 TGF 期间收缩，并且 Ef-Art 对血管活性物质的反应 激素受肾小球产生的旁分泌因子调节。因此 肾脏微循环的控制是复杂且难以检查的 体内。因此，我们建议使用我们开发的技术 由显微解剖的 Af- 或 Ef-Art 的体外灌注和粘附组成 包含致密斑的管状部分。使用这种制剂，我们 假设不同的和传出的阻力是由自分泌调节的 以及从肾小球和致密斑释放的旁分泌因子。 促进扩张的因素包括 NO、前列腺素 (PG) 和 5,6 环氧二十碳三烯酸（EET）。这些因素被以下因素所抵消 促进血管收缩，包括 Ang II、血栓素、20- 羟基二十碳四烯酸（HETE）和活性氧。旁分泌 腺苷等因子可能具有扩张或收缩作用，具体取决于 A1 或 A2 受体是否在靶组织上表达。在目标 1 中，我们 将检验当黄斑致密区 nNOS 增加时的假设，例如 低盐摄入期间，致密斑释放的 NO 调节基础 Af-Art 即使致密斑中的 NaCl 水平非常低，也能产生抵抗力。在这个 在这种情况下，NO 不仅作用于致密斑，而且还通过从 致密黄斑到 Af-Art 引起扩张，从而保护肾 尽管肾素水平较高，但仍存在血流量。在目标 2 中，我们将检验以下假设： 淬灭由致密斑释放的 NO nNOS、O2- 决定了 a) 的大小 TGF 和 b) NO 是否仅以自分泌方式在致密斑中起作用 本身，或者也可以通过扩散到 Af-Art 并引起旁分泌模式 扩张。在目标 3 中，我们将检验细胞内增加的假设 致密斑中的钙通过促进 致密斑 ATP 的释放和间质中腺苷的形成 通过激活 nNOS 来调节 TGF 的空间和负调节因子。在目标 4 中，我们将 检验肾小球释放旁分泌因子的假设 控制下游 Ef-Art 阻力，从而控制其自身的过滤 压力。在目标 5 中，我们将检验以下假设：Ef-Art 的机制 TGF 与 Af-Art TGF 类似，只是腺苷作用于 Ef-Art A2 受体，引起扩张。因此，通过抑制 nNOS 来减少 NO 致密黄斑将增强 Ef-Art TGF（更大扩张）。