# Epithelial Sodium Channel Trafficking

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2020 · —

## Abstract

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.

## Key facts

- **NIH application ID:** 9864021
- **Project number:** 5I01BX001862-07
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Peter M Snyder
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-04-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864021

## Citation

> US National Institutes of Health, RePORTER application 9864021, Epithelial Sodium Channel Trafficking (5I01BX001862-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864021. Licensed CC0.

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