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：（申请人提供） 在高血压中，无论其原因如何，肾血管阻力增加， 使压力尿钠排泄曲线向右移动。Af-Art（英语：Af-Art） 而输出小动脉（Ef-Art）是肾血管阻力的主要来源; 它们控制肾小球滤过率（GFR）和管周压， 从而影响肾功能。Af-和Ef-Art电阻由一个 血管加压素（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，腺苷通过A2 受体）。Af-Art还受肾小管肾小球反馈（TGF）控制。 TGF通过感受Cl-、Na+和/或溶质负荷的致密斑起作用 并将旁分泌信号发送到肾小球外系膜细胞和/或 TGF的效应物，其是Af-Art和Ef-Art。除了TGF 信号本身，致密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， 分别一氧化氮由致密斑神经元一氧化氮合酶（nNOS）产生， 减弱TGF β，是一种这样的自体素。我们有证据表明Ef-Art扩张 而不是在TGF过程中收缩，并且Ef-Art对血管活性物质的反应 激素由肾小球产生的旁分泌因子调节。因此 肾微循环的控制是复杂的， vivo.因此，我们建议使用我们开发的一种技术， 由体外灌注显微切割的Af-或Ef-Art和粘附的 包含致密斑的管状部分。使用该制剂，我们 假设不同和传出抗性受自分泌调节 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（PGs）和5，6 环氧二十碳三烯酸（EET）。这些因素相互抵消， 促进血管收缩，包括血管紧张素II，血栓素，20- 羟基二十碳四烯酸（HETE）和活性氧。旁分泌 诸如腺苷的因子可具有扩张或收缩作用，这取决于 A1或A2受体是否在靶组织上表达。在目标1中， 将检验假设，即当致密斑nNOS增加时，例如 在低盐摄入期间，致密斑释放的NO调节基础Af-Art 即使当致密斑中的NaCl水平非常低时，也可以抵抗。在这 在这种情况下，NO不仅作用于致密斑，而且还通过从致密斑扩散， 致密斑到Af-Art，在那里它引起扩张，从而保留肾脏 尽管高肾素血液流动。在目标2中，我们将检验以下假设： 猝灭致密斑nNOS释放的NO，O2-决定a） 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，我们将测试细胞内增加的假设， 致密斑中的钙既作为正调节剂， 向致密斑释放ATP并在间质中形成腺苷 空间和TGF的负调节因子通过激活nNOS。在目标4中， 检验肾小球释放旁分泌因子的假设， 控制下游Ef-Art阻力，从而控制自身过滤 压力在目标5中，我们将测试Ef-Art的机制 TGF类似于Af-Art TGF，除了腺苷作用于Ef-Art A2 受体，导致扩张。从而通过抑制细胞中的nNOS来减少NO。 致密斑将增强Ef-Art TGF（更大的扩张）。