Regulation of the Renal Microcirculation by the Connecting Tubule

在高血压中，压力尿钠排泄设定点被转移到更高的压力，由于两者的增加， 肾血管阻力和Na+重吸收。输入小动脉（Af-Art）和输出小动脉占 对于大多数肾血管阻力;它们控制肾小球滤过率（GFR）和管周压， 从而影响肾功能。Af-Art抵抗力受到类似于控制其他药物的因素的调节。 此外，Af-Art还受肾小管肾小球反馈（TGF）控制。TGF通过 macula densa，它感觉到NaCl的增加，并发出一个信号，收缩Af-Art。 证据表明，增加NaCl输送到连接小管（CNT）扩张Af-Art，这种扩张 可以被Na+转运抑制剂阻断。我们把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。我们亦会研究 一氧化氮（NO）和肾小管肾素-血管紧张素系统（RAS）调节CTGF，因为NO 合成酶以及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 连接小管对Na+的重吸收诱导Na+释放的一般假设 花生四烯酸代谢物，其扩散至Af-Art并促进Af-Art的扩张（CTGF反应）。 因此，CTGF拮抗血管收缩刺激，如TGF。肾小管RAS通过以下途径增强CTGF 刺激CNT的Na+转运，而NO通过抑制这一过程来削弱CTGF。我们将测试这个 四个目标的一般假设。目的我将测试是否增加钠+重吸收的CNT引起的， 通过Na+/ Ca++交换器增加细胞内Ca++，导致Ca++介导的 磷脂酶，花生四烯酸的释放，以及扩散到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，以及是否 在没有TGF的情况下，CTGF引起Af-Art扩张。Aim III将测试NOS 3是否产生NO， CNT通过经由鸟苷酸环化酶的活化阻断ENaC的Na+转运，增加cGMP， 激活cGMP依赖性蛋白激酶，并降低cAMP。Aim IV将测试管状RAS是否通过 Ang II和AT 1受体通过直接作用于ENaC和间接刺激ENaC来增强CTGF。 通过NADPH氧化酶释放O2-。这将是第一个研究，以确定肾连接小管的作用，在调节传入 小动脉阻力和肾小球滤过率。这是一个新的机制，将提供新的见解， 肾功能的调节。

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.