Epithelial Sodium Channel Trafficking

肾脏上皮性钠离子通道(ENaC)表达的调节对 维持细胞外Na+和容量动态平衡。这反过来又扮演着重要的角色。 在血压控制方面，正如观察到的ENaC突变导致遗传 高血压(利德尔综合征)和低血压(PHA 1型)。的总目标是 我们的建议是阐明调控ENaC的信号机制和运输途径。 在前一个资金阶段工作的基础上，我们将专注于一种新的信号通路 在高血糖的情况下管制ENaC的贩运。先前的工作表明， 糖尿病患者远端肾单位对Na+的吸收增强，ENaC 丰富度增加了。这可以用来对抗Na+和由 高血糖症。此外，糖尿病和高血压之间存在着关键的联系。 高血压在糖尿病患者中的发病率是普通人群的两倍，而且 显著增加心血管并发症的风险。先前的研究表明， 肾脏Na+重吸收过多在糖尿病发病机制中的作用 高血压。然而，糖尿病和高血压之间的潜在机制也 因为解释ENaC丰度增加的机制尚未确定。在这 通过这项提议，我们将解决我们知识中的这一严重差距。在初步研究中，我们发现 集合管上皮细胞暴露于高糖可增加ENAC电流 在糖尿病患者体内的浓度范围内。血糖升高 电流通过增加细胞表面的ENaC丰度来实现。其他初步数据支持 E3泛素连接酶Nedd4-2在这一调节中的作用。基于这些发现，我们建议 高血糖通过改变Nedd4-2-增加肾脏对Na+的吸收的总体假说 受管制的ENaC贩运。我们提出了三个具体的目标来测试这个模型。这项工作有 确定糖尿病和血容量紊乱之间的机制联系的可能性 高血压背后的动态平衡，以及我们对它们是如何相互关联的理解。

Regulation of epithelial Na+ channel (ENaC) expression in the kidney is critical to the maintenance of extracellular Na+ and volume homeostasis. This in turn plays an important role in blood pressure control, as illustrated by the observation that ENaC mutations cause inherited forms of hypertension (Liddle's syndrome) and hypotension (PHA type 1). The overall goal of our proposal is to elucidate signaling mechanisms and trafficking pathways that regulate ENaC. Building on our work in the previous funding period, we will focus on a novel signaling pathway that regulates ENaC trafficking under conditions of hyperglycemia. Previous work indicates that in diabetes mellitus, renal Na+ absorption in the distal nephron is enhanced, and ENaC abundance is increased. This may serve to counter Na+ and volume wasting induced by hyperglycemia. Moreover, there is a critical link between diabetes mellitus and hypertension. Hypertension is two-fold more common in diabetics than in the general population and it dramatically increases the risk for cardiovascular complications. Previous work suggests a causative role for excessive renal Na+ reabsorption in the pathogenesis of diabetes-associated hypertension. However, the underlying mechanisms linking diabetes and hypertension, as well as the mechanisms to explain enhanced ENaC abundance, have not been identified. In this proposal, we will address this critical gap in our knowledge. In preliminary studies, we found that ENaC current was increased by exposure of collecting duct epithelia to elevated glucose concentrations within the range found in patients with diabetes mellitus. Glucose increased current by increasing ENaC abundance at the cell surface. Additional preliminary data support a role for an E3 ubiquitin ligase, Nedd4-2, in this regulation. Based on these findings, we propose an overall hypothesis that hyperglycemia increases renal Na+ absorption by altering Nedd4-2- regulated trafficking of ENaC. We propose three specific aims to test this model. This work has the potential to define a mechanistic link between diabetes and the disrupted volume homeostasis that underlies hypertension, and on our understanding of how they are interrelated.