Regulation of Pendrin by Angiotensin II

在代谢性碱中毒期间，B型嵌入细胞主动分泌HCO3-，并通过 顶端质膜，通过CI-/HCO3-交换器，悬垂环。其结果是衰减了 碱血症。吊环蛋白介导的氯离子吸收也是血管体积的一个重要机制 在NACI敏感型高血压啮齿动物模型中观察到的扩张和高血压，如下 给予高NaCI饮食和醛固酮类似物。因此，氯离子的运输过程，如 在盐敏感型高血压的发生中起重要作用。我们的实验室有证据表明 血管紧张素II不依赖于醛固酮，直接调节侧膜蛋白介导的氯离子摄取。此外，在 Ccd，血管紧张素11介导的NaCI吸收增加可能需要两者的协调作用 垂蛋白和上皮性Na+通道，ENaC。黄曲霉毒素对支链蛋白调控的分子机制 血管紧张素II以及ENaC和侧耳蛋白如何相互作用来调节NaCI的吸收是目前的主题 求婚。这项提议的目的是1)确定血管紧张素II刺激血管紧张素的机制 垂垂蛋白在体外介导的CI-/HCO3-交换及其与ENaC的相互作用 血管紧张素II促进NaCI吸收。2)确定长效调控机制 血管紧张素所致的垂体素。3)确定了Pendrin与ENaC相互依赖的机制 表情。为了实现这些目标，将对SLC26A4(+/+)和SLC26A4(-/-)小鼠进行研究 实时定量聚合酶链式反应、免疫组织化学、免疫金细胞化学、 体外灌流肾小管免疫印迹和转运研究。整体动物研究将进一步 用于平衡研究和测量血压和肾小球滤过率。 篇章摘要：我们的实验室观察到一种促进体内氯离子吸收的蛋白质--吊环蛋白 肾脏在高血压的产生中起着重要的作用。此外，吊环蛋白的活性非常高。 依赖于一种称为ENaC的特定肾脏钠转运体的活性。这份提案将探讨如何 吊环蛋白控制肾脏对氯离子的吸收以及为什么吊环蛋白和ENaC的活性如此依赖于 彼此之间。

During metabolic alkalosis, the type B intercalated cell actively secretes HCO3- and absorbs Cl- across the apical plasma membrane, through the CI-/HCO3- exchanger, pendrin. The result is attenuation of the alkalemia. Pendrin-mediated Cl- absorption is also an important mechanism for the vascular volume expansion and hypertension observed in rodent models of NaCI-sensitive hypertension, such as following the administration of a high NaCI diet and aldosterone analogues. Thus Cl- transport processes, such as pendrin, are critcal in the generation of salt-sensitive hypertension. Our laboratory has evidence that angiotensin II directly regulates pendrin-mediated Cl- uptake, independent of aldosterone. Moreover, in the CCD, the angiotensin ll-mediated increase in NaCI absorption likely requires the coordinated action of both pendrin and the epithelial Na+ channel, ENaC. The molecular mechanism for the regulation of pendrin by angiotensin II and how ENaC and pendrin interact to mediate NaCI absorption is the subject of the present proposal. The aims of this proposal are 1) To determine the mechanism whereby angiotensin II stimulates pendrin-mediated CI-/HCO3- exchange in vitro and to determine how pendrin and ENaC interact following angiotensin II to increse NaCI absorption. 2) To determine the mechanism of the long-term regulation of pendrin by angiotensin. 3) To determine the mechanism of the interdependency of pendrin and ENaC expression. To accomplish these objectives Slc26a4 (+/+) and Slc26a4 (-/-) mice will be studied using quantitative real time PCR, light microscopic immunonistochemistry, immunogold cytochemistry, immunoblots and transport studies in vitro in perfused renal tubules . Whole animal studies will be further employed in balance studies and measurements of blood pressure and GFR. Lay summary: Our laboratory has observed that pendrin, a protein that promotes absorption of chloride in the kidney, is important in the generation of high blood pressure. In addition, activity of pendrin is very dependent on activity of a specific kidney sodium transporter, called ENaC. This proposal will explore how pendrin controls absorption of Cl- by the kidney and why activity of pendrin and ENaC are so dependent on each other.