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: 8034726
• 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 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034726
• 关键词: AGTR2 gene; Accounting; Acids; Amiloride; Angiotensin II; Angiotensinogen; Arachidonic Acids; 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

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.

在高血压中，由于两者的增加 肾血管耐药性和NA+重吸收。传入小动脉（AF-ART）和传出小动脉帐户 对于大多数肾脏血管抗性；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-Art抗性受到与控制其他的因素相似的因素 小动脉；另外，AF-ART还由肾小管斜体反馈（TGF）控制。 TGF通过 Macula densa感应在NaCl中增加并发送缩减AF-ART的信号。我们有 增加NaCl向连接小管（CNT）递送的证据可以扩张AF-ART，并且这种扩张 可以被Na+转运的抑制剂阻塞。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 确定其生理作用和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）调节CTGF 合成酶，肾素和血管紧张素原在肾单位中表达。在体外和体内我们建议测试 一般假设，即通过连接小管重吸收Na+会引起释放 花生四烯酸代谢产物扩散并促进AF-ART扩张（CTGF反应）。 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，而没有通过抑制此过程来钝化CTGF。我们将测试这个 四个目标中的一般假设。目的我将测试CNT中Na+重吸收的增加是否导致 通过Na+/ Ca ++交换器增加细胞内Ca ++，从而导致Ca ++介导的激活 磷脂酶，蛛网膜酸的释放以及eicosanoids的形成，它们扩散到AF-ART和AF-ART和 引起扩张。 AIM II将测试In Vivo，CTGF是否反对TGF的血管收缩效应以及是否反对 在没有TGF的情况下，CTGF会导致Af-Art扩张。 AIM III将测试NOS 3在 CNT通过激活Guanylyl Cyclase通过ENAC阻断Na+传输来降低CTGF，从而增加CGMP， 激活CGMP依赖性蛋白激酶，并减少营地。 AIM IV将测试管状RAS是否通过 ANG II和AT1受体直接通过对ENAC作用并间接通过刺激来增强CTGF 通过NADPH氧化酶释放O2-。这将是确定肾脏连接小管在调节传入中的作用的第一项研究 动脉抗性和肾小球滤过速率。这是一种新颖的机制，可以提供新的见解 肾功能的调节。