Regulation of the Renal Microcirculation by the Connecting Tubule

连接小管对肾脏微循环的调节

• 批准号: 7580940
• 负责人: Oscar A. Carretero
• 金额: $ 32.63万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-07 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7580940
• 关键词: AGTR2 gene; Accounting; Acids; Amiloride; Angiotensin II; Angiotensinogen; Arachidonic Acids; Arts; Blood; Bradykinin; Chelating Agents; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diffuse; Dilatation - action; Distal; Eicosanoids; Equilibrium; Feedback; Furosemide; Glomerular Filtration Rate; Guanylate Cyclase; Hydrochlorothiazide; Hypertension; In Vitro; Kidney; Kinins; Macula densa; Measures; Mediating; Microcirculation; Micropuncture; Morphology; Mus; NADPH Oxidase; Natriuresis; Nephrons; Nitric Oxide; Nitric Oxide Synthase; Norepinephrine; Perfusion; Phospholipase; Physiological; Play; Preparation; Process; Prostaglandins; Protein Isoforms; Protein Kinase Inhibitors; Regulation; Renal function; Renin; Renin-Angiotensin System; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Side; Signal Transduction; Soluble Guanylate Cyclase; Stimulus; Techniques; Testing; Thromboxane A2; Tubular formation; Vascular resistance; Vasoconstrictor Agents; Vasodilation; acetovanillone; arteriole; benzamil; channel blockers; epithelial Na+ channel; in vivo; inhibitor/antagonist; insight; kidney cortex; kidney vascular structure; novel; pressure; protein kinase inhibitor; receptor; response; vasoconstriction

DESCRIPTION (provided by applicant): In hypertension the pressure natriuresis set point is shifted to a higher pressure, due to an increase in both renal vascular resistance and Na+ reabsorption. The afferent arterioles (Af-Art) and efferent arterioles account for most renal vascular resistance; they control glomerular filtration rate (GFR) and peritubular pressure, and consequently renal function. Af-Art resistance is regulated by factors similar to those that control other arterioles; in addition, the Af-Art is also controlled by tubuloglomerular feedback (TGF). TGF operates via the macula densa, which senses increases in NaCl and sends a signal that constricts the Af-Art. We have evidence that increasing NaCl delivery to the connecting tubule (CNT) dilates the Af-Art, and that this dilatation can be blocked by inhibitors of Na+ transport. We refer to the cross-talk between the CNT and Af-Art as connecting tubule glomerular feedback (CTGF). Here we propose to study CTGF both in vitro and in vivo to determine its physiological role and the mechanisms by which Na+ causes CTGF. We will also study the regulation of CTGF by nitric oxide (NO) and the tubular renin-angiotensin system (RAS), since both NO synthase and renin and angiotensinogen are expressed in the nephron. In vitro and in vivo we propose to test the general hypothesis that Na+ reabsorption by the connecting tubule induces the release of arachidonic acid metabolites that diffuse to and promote dilatation of the Af-Art (CTGF response). Thus CTGF antagonizes vasoconstrictor stimuli such as TGF. The tubular RAS potentiates CTGF by stimulating Na+ transport by the CNT, while NO blunts CTGF by inhibiting this process. We will test this general hypothesis in four Aims. Aim I will test whether an increase in Na+ reabsorption in the CNT causes an increase in intracellular Ca++ via the Na+/ Ca++ exchanger, which results in Ca++-mediated activation of phospholipases, release of arachidonic acid, and formation of eicosanoids which diffuse to the Af-Art and cause dilatation. Aim II will test whether in vivo, CTGF opposes the vasoconstrictor effect of TGF and whether in the absence of TGF, CTGF causes Af-Art dilatation. Aim III will test whether NO produced by NOS 3 in the CNT decreases CTGF by blocking Na+ transport by ENaC via activation of guanylyl cyclase, increasing cGMP, activating cGMP-dependent protein kinase, and reducing cAMP. Aim IV will test whether the tubular RAS via Ang II and the AT1 receptor enhances CTGF directly by acting on ENaC and indirectly by stimulating the release of O2- via NADPH oxidase. This will be the first study to determine the role of the renal connecting tubule in the regulation of afferent arteriole resistance and glomerular filtration rate. This is a novel mechanism that will provide new insights on the regulation of renal function.

描述（由申请人提供）：在高血压中，由于肾血管耐药性和Na+重吸收的增加，压力纳地尿液设定点被转移到更高的压力。传入小动脉（Af-Art）和传出小动脉占大多数肾血管抗性；他们控制肾小球滤过率（GFR）和周围压力，因此是肾功能。 Af-Art耐药性受到与控制其他动脉的因素相似的因素。另外，AF-ART还由肾小管斜体反馈（TGF）控制。 TGF通过黄斑densa运行，该Macula densa在NaCl中感应增加，并发送一个限制AF-ART的信号。我们有证据表明，将NaCl递送到连接小管（CNT）的递送增加了AF-ART-AF-ART，并且可以通过Na+转运的抑制剂阻断这种扩张。我们将CNT和AF-ART之间的串扰称为连接小管肾小球反馈（CTGF）。在这里，我们建议在体外和体内研究CTGF，以确定其生理作用以及Na+引起CTGF的机制。我们还将研究通过一氧化氮（NO）和管状肾素 - 血管紧张素系统（RAS）对CTGF的调节，因为在肾单位中均表达了NONNATTHASE，NO NONSTHASE，NON肾素以及肾素和血管紧张素原。在体外和体内，我们建议检验一个总体假设，即连接小管通过连接小管重吸收可诱导蛛网膜酸代谢产物的释放，从而扩散并促进AF-ART的扩张（CTGF响应）。因此，CTGF拮抗血管收缩刺激，例如TGF。管状Ras通过通过CNT刺激Na+转运来增强CTGF，而没有通过抑制此过程来钝化CTGF。我们将在四个目标中检验这一普遍假设。目的我将测试CNT中Na+重吸收的增加是否会通过Na+/ Ca ++交换器增加细胞内Ca ++的增加，从而导致Ca ++介导的磷脂酶的激活，蛛网膜酸的释放，并形成eicosanoids，而eicosanoids则使Af-Art-Af-Art-Art-Art-Art-Artaids的形成。 AIM II将测试IN VIVO，CTGF是否反对TGF的血管收缩效应，以及在没有TGF的情况下，CTGF是否会导致Af-Art扩张。 AIM III将测试CNT中NOS 3产生的NO是否通过通过激活Guanylyl Cyclase来阻止Na+转运，从而降低CTGF，从而增加CGMP，从而激活CGMP依赖性蛋白激酶和减少CAMP。 AIM IV将通过ANG II和AT1受体直接通过对ENAC作用并间接地通过刺激O2-通过NADPH氧化酶释放来增强CTGF。这将是确定肾连接小管在调节传入小动脉抗性和肾小球滤过率中的作用的第一项研究。这是一种新型机制，将为调节肾功能提供新的见解。