Epithelial Na+ Channel Activation after Bile Duct Ligation with Mineralocorticoid Receptor Blockade

Abstract

Key Points Bile acids activate the epithelial Na+ channel (ENaC), which may lead to subsequent fluid retention in liver disease.Bile duct ligation with spironolactone increased ENaC-dependent Na+ and fluid retention without hormone-linked increased ENaC abundance.Counteracting bile acid ENaC activation may be effective for treating fluid retention in liver disease. Background Sodium and fluid retention in liver disease is classically thought to result from reduced effective circulating volume and stimulation of the renin-angiotensin-aldosterone system. However, evidence of fluid retention in patients without renin-angiotensin-aldosterone system activation suggests the involvement of additional mechanisms. In vitro, bile acids activate the epithelial Na+ channel (ENaC) found in the aldosterone-sensitive distal nephron. If this occurs in vivo, ENaC may become activated in liver disease even with antagonism of aldosterone signaling. Methods To test this, we performed bile duct ligation to induce liver disease and increase circulating bile acids in mice given spironolactone to antagonize aldosterone signaling. We analyzed effects on blood, urine, and body composition. We also determined the effects of taurocholic acid, a primary conjugated bile acid elevated in liver disease, on ion fluxes in microperfused rabbit collecting ducts. Results Bile duct ligation increased benzamil-sensitive natriuresis compared with sham, indicating ENaC activation. These effects were not explained by effects on ENaC expression, cleavage, or localization. Bile duct–ligated mice also gained significantly more fluid than sham-operated animals. Blocking ENaC reversed fluid gains in bile duct–ligated mice but had no effect in shams. In dissected collecting ducts from rabbits, which express ENaC, taurocholic acid stimulated net Na+ absorption. Conclusions Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease.