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，由于肾血管阻力和Na+重吸收增加，压力尿钠排泄设定点转移至更高的压力。传入小动脉（Af-Art）和传出小动脉占大多数肾血管阻力;它们控制肾小球滤过率（GFR）和管周压，从而控制肾功能。Af-Art阻力受与控制其他小动脉的因素类似的因素调节;此外，Af-Art还受肾小管肾小球反馈（TGF）控制。TGF通过致密斑，其感觉增加在NaCl和发送信号，收缩的Af-Art。我们有证据表明，增加NaCl输送到连接小管（CNT）扩张的Af-Art，这种扩张可以通过Na+转运抑制剂阻断。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，以确定其生理作用和机制，Na+导致CTGF。我们还将研究一氧化氮（NO）和肾小管肾素-血管紧张素系统（RAS）对CTGF的调节，因为NO合酶、肾素和血管紧张素原都在肾单位中表达。在体外和体内，我们建议测试的一般假设，Na+重吸收的连接小管诱导释放的花生四烯酸代谢产物扩散到并促进扩张的Af-Art（CTGF反应）。因此，CTGF拮抗血管收缩刺激，如TGF。肾小管RAS通过刺激CNT的Na+转运来增强CTGF，而NO通过抑制该过程来钝化CTGF。我们将在四个目标中检验这个一般假设。目的我将测试是否增加在CNT中的Na+重吸收引起细胞内Ca++通过Na+/ Ca++交换，这导致在Ca++介导的磷脂酶的激活，花生四烯酸的释放，并形成类花生酸扩散到Af-Art和引起扩张。目的II将测试在体内，CTGF是否对抗TGF的血管收缩作用，以及在没有TGF的情况下，CTGF是否引起Af-Art扩张。目的III将检测CNT中NOS 3产生的NO是否通过激活鸟苷酸环化酶、增加cGMP、激活cGMP依赖性蛋白激酶和减少cAMP来阻断ENaC的Na+转运，从而降低CTGF。目的IV将检测肾小管RAS是否通过Ang II和AT 1受体直接作用于ENaC和通过NADPH氧化酶刺激O2-释放间接增强CTGF。这将是第一个研究，以确定在传入小动脉阻力和肾小球滤过率的调节肾连接小管的作用。这是一种新的机制，将为肾功能的调节提供新的见解。