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，肾血管抗性增加， 将压力纳地液曲线转移到右侧。传入（Af-Art） 大多数肾血管耐药性和传出小动脉（EF-ART）占据； 他们控制肾小球滤过率（GFR）和周围压力，以及 因此是肾功能。 AF和EF-ART电阻受A调节 加压剂（通过A1受体，血管紧张素，腺苷，腺苷）之间的平衡， 活性氧）和血管抑制剂（Kinins，NO，通过A2的腺苷 受体）。 AF-ART还由肾小管斜体反馈（TGF）控制。 TGF通过Macula densa操作，该大黄斑会感受到Cl-，Na+和/或溶质负载 并将旁分泌信号发送到外部细胞和/或 TGF的效应子，是AF-ART和EF-ART。除了TGF 信号本身，黄斑丹萨产生自分泌和旁分泌因素 通过在黄斑densa或Af-和ef-Art上作用，改变TGF 分别。 Macula densa神经元NO合酶（NNOS）生产的NO，它 衰减TGF，就是这样的自闭症。我们有证据表明EF-ART扩张 而不是在TGF期间收缩，而EF-ART对血管活性的反应 激素是由肾小球产生的旁分泌因子调节的。因此 肾脏微循环的控制是复杂的，难以检查 体内。因此，我们建议使用一种我们开发的技术 由微解析的AF或EF-ART和粘附的体外灌注组成 含有黄斑的丹森的管状段。使用此准备，我们 假设不同和发出的耐药性受自分泌的调节 肾小球和黄斑densa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 环氧树钠酸（EET）。这些因素与 促进血管收缩，包括Ang II，血栓烷，20- 羟基乙烯烯酸（Hete）和活性氧。旁分线 腺苷之类的因素可能会根据 A1还是A2受体在靶组织上表达。在目标1中我们 将检验以下假设：当黄斑densa nnos增加时，例如 在低盐摄入量中，黄斑densa不释放 即使黄斑丹森的NaCl水平非常低，电阻也是如此。在这个 情况，不仅在黄斑丹萨（Macula densa 黄斑丹萨（Macula densa 尽管肾素很高，但血液流动。在AIM 2中，我们将检验以下假设 macula densa nnos，o2-确定a）大小 TGF和B）是否仅在黄斑丹萨（Macula Densa）中不以自分泌方式行事 本身，或以旁分泌模式扩散到AF-ART并引起 扩张。在AIM 3中，我们将检验以下假设，即细胞内增加 黄斑丹森（Macula densa）中的钙通过贡献作为阳性调节剂 在间隙中释放ATP和腺苷的形成的黄斑densa 通过激活NNOS的空间和TGF的负调节剂。在目标4中，我们将 测试肾小球释放旁分泌因子的假设 控制下游EF-ART抗性，因此其自身过滤 压力。在AIM 5中，我们将检验以下假设。 TGF与Af-Art TGF相似，除了腺苷作用于EF-ART A2 受体，导致扩张。从 黄斑densa将增强EF-ART TGF（更大的扩张）。