Regulation of Pendrin by Angiotensin II

在代谢过程中，B型插层细胞主动分泌HCO 3-并吸收Cl-穿过 顶端质膜，通过Cl-/HCO 3-交换器，pendrin。其结果是， 碱血症Pendrin介导的Cl-吸收也是血管容积的重要机制 在NaCl敏感性高血压的啮齿动物模型中观察到的扩张和高血压，例如以下 给予高氯化钠饮食和醛固酮类似物。因此，Cl-运输过程，如 pendrin在盐敏感性高血压的产生中起关键作用。我们的实验室有证据表明 血管紧张素II直接调节pendrin介导的Cl-摄取，不依赖于醛固酮。而且在 CCD，血管紧张素II介导的NaCl吸收增加可能需要两者的协调作用 pendrin和上皮Na+通道ENaC。pendrin调控的分子机制 血管紧张素II以及ENaC和pendrin如何相互作用以介导NaCl吸收是本发明的主题。 提议本提案的目的是1）确定血管紧张素II刺激血管紧张素受体的机制。 pendrin介导的Cl-/HCO 3-交换，并确定pendrin和ENaC如何在 血管紧张素II增加NaCl吸收。2)确定长期调控机制， pendrin血管紧张素。3)确定pendrin和ENaC相互依赖的机制 表情为了实现这些目的，将使用以下方法研究Slc 26 a4（+/+）和Slc 26 a4（-/-）小鼠： 定量真实的时间PCR，光镜免疫组化，免疫金细胞化学， 免疫印迹和体外灌注肾小管转运研究。整个动物研究将进一步 用于平衡研究和测量血压和GFR。 简单总结：我们的实验室已经观察到，pendrin，一种促进氯化物吸收的蛋白质， 肾脏在高血压的产生中起着重要作用。此外，pendrin的活性非常 这取决于一种叫做ENaC的特殊肾脏钠转运蛋白的活性。本提案将探讨如何 pendrin控制肾脏对Cl-的吸收，以及为什么pendrin和ENaC的活性如此依赖于 对方.

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.