# ENaC regulation by biliary factors

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $450,283

## Abstract

Patients with advanced liver disease often experience fluid retention and electrolyte disturbances
due in part to activation of the renin-angiotensin-aldosterone system. Aldosterone activates the
epithelial Na+ channel (ENaC) in the distal nephron, enhancing urinary Na+ retention and K+
excretion. But many liver disease patients experience fluid retention without apparent activation
of the renin-angiotensin-aldosterone system. Liver disease patients also frequently exhibit
elevated plasma bile acids and hyperbilirubinemia. Preliminary data show that specific bile acids
and conjugated bilirubin activate ENaC in vitro and that taurocholic acid activates ENaC in
isolated collecting ducts. The central hypothesis of our proposal is that urinary bile acids and
possibly conjugated bilirubin directly activate ENaC, promoting Na+ and fluid retention and K+
excretion. The goal of this proposal is to determine whether this regulation occurs in vivo and to
determine the molecular mechanism of regulation. Preliminary data suggest that urine from
patients with alcoholic hepatitis contains concentrations of activating bile acids and conjugated
bilirubin sufficient to activate the channel, and indeed activate the channel. We will determine
whether urine from alcoholic hepatitis patients activates ENaC in experimental cells. We further
hypothesize that elevated biliary factors activate ENaC in the distal nephron, promoting Na+
retention and K+ excretion. We will test this hypothesis in isolated collecting ducts. We will also
test this hypothesis in vivo by chronically administering biliary factors and quantifying changes in
weight, blood K+, urinary Na+ and K+, plasma aldosterone, and total body water. Preliminary data
suggest that taurocholic acid promotes Na+ retention, K+ loss, and volume expansion. We will
determine the contribution of ENaC to observed changes by using drugs to block ENaC, and by
using genetic changes to increase the channel's sensitivity to biliary factors or to decrease ENaC's
contribution to renal Na+ and K+ handling. Experiments will also investigate the molecular
mechanism of ENaC regulation by bile acids. We hypothesize that activating bile acids interact
directly with the channel to enhance channel activity. We will use derivatized bile acids to detect
direct binding, and key chemical and biophysical properties of the both the channel and bile acids
to dissect the interaction. Key experiments will be performed in multiple cell models, including
Xenopus oocytes, cultured epithelial cells, and mouse collecting ducts. Direct ENaC activation by
biliary factors elevated in liver disease has not been previously investigated, and may contribute
to the volume overload, edema, and electrolyte imbalances associated with liver disease.

## Key facts

- **NIH application ID:** 10440329
- **Project number:** 5R01DK125439-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** OSSAMA B KASHLAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $450,283
- **Award type:** 5
- **Project period:** 2020-07-21 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440329

## Citation

> US National Institutes of Health, RePORTER application 10440329, ENaC regulation by biliary factors (5R01DK125439-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10440329. Licensed CC0.

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