Epithelial Sodium Channel Trafficking

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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.