Epithelial Sodium Channel Trafficking

上皮钠通道贩运

• 批准号: 9450665
• 负责人: Peter M Snyder
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9450665
• 关键词: Address; Animals; Binding; Binding Sites; Blood Pressure; Cardiovascular Diseases; Cell membrane; Cell surface; Data; Defect; Diabetes Mellitus; Disease; Distal; Ductal Epithelium; Funding; General Population; Glucose; Goals; Homeostasis; Hyperglycemia; Hypertension; Hypotension; Individual; Inherited; Ion Channel; Kidney; Knockout Mice; Knowledge; Link; Maintenance; Mediating; Modeling; Modification; Molecular; Mutation; Myocardial Infarction; Nephrons; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Play; Population; Regulation; Role; Signal Pathway; Signal Transduction; Site; Sodium; Syndrome; Testing; Ubiquitination; Veterans; Work; absorption; base; blood pressure regulation; cardiovascular risk factor; diabetic; effective therapy; epithelial Na+ channel; extracellular; knock-down; novel; protein function; response; small molecule inhibitor; stem; stroke risk; trafficking; ubiquitin-protein ligase; uptake; wasting

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.

肾脏中上皮Na+通道（ENaC）表达的调节对肾脏的功能至关重要。 维持细胞外Na+和容量稳态。这反过来又起着重要的作用 在血压控制方面，如观察到ENaC突变引起遗传性高血压， 高血压（Liddle综合征）和低血压（PHA 1型）。的总目标 我们的建议是阐明调控ENaC的信号传导机制和运输途径。 基于我们在上一个资助期的工作，我们将专注于一个新的信号通路 在高血糖条件下调节ENaC运输。以前的工作表明， 在糖尿病中，远端肾单位的肾Na+吸收增强，ENaC 丰度增加。这可能有助于对抗Na+和容量消耗诱导的 高血糖症此外，糖尿病和高血压之间存在着重要的联系。 高血压在糖尿病患者中的发病率是普通人群的两倍， 大大增加了心血管并发症的风险。以前的工作表明， 肾脏Na+重吸收过度在糖尿病相关性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， 作为解释ENaC丰度增加的机制，尚未确定。在这 在我们的建议中，我们将解决我们知识中的这一关键差距。在初步研究中，我们发现， 收集管上皮细胞暴露于高浓度葡萄糖可增加ENaC电流 在糖尿病患者中发现的范围内的浓度。葡萄糖升高 通过增加细胞表面的ENaC丰度来增加电流。其他初步数据支持a E3泛素连接酶Nedd 4 -2在此调节中的作用。基于这些发现，我们建议 总体假设是高血糖症通过改变Nedd 4 -2- 管制ENaC的贩运。我们提出了三个具体目标来测试这个模型。这项工作 确定糖尿病和破坏体积之间的机械联系的可能性 高血压背后的内稳态，以及我们对它们如何相互关联的理解。