ctivation 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....

中文翻译：

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盐皮质激素受体阻断胆管结扎后上皮 Na + 通道激活


CTIVATION 可能对治疗肝病中的液体潴留有效。背景 肝病中的钠和液体潴留通常被认为是由于有效循环量减少和肾素-血管紧张素-醛固酮系统刺激所致。然而，没有肾素-血管紧张素-醛固酮系统激活的患者体液潴留的证据表明还涉及其他机制。在体外，胆汁酸激活醛固酮敏感的远端肾单位中的上皮 Na + 通道 （ENaC）。如果这种情况发生在体内，即使醛固酮信号传导拮抗，ENaC 也可能在肝病中被激活。方法 为了测试这一点，我们进行了胆管结扎术以诱导肝病并增加给予螺内酯以拮抗醛固酮信号传导的小鼠的循环胆汁酸。我们分析了对血液、尿液和身体成分的影响。我们还确定了牛磺胆酸（一种在肝病中升高的初级共轭胆汁酸）对微灌注兔集合管中离子通量的影响。结果 与假手术相比，胆管结扎术增加了苯扎米敏感性利钠，表明 ENaC 激活。这些影响不能用对 ENaC 表达、切割或定位的影响来解释。胆管结扎的小鼠也比假手术的动物获得更多的液体。阻断 ENaC 可逆转胆管结扎小鼠的液体增加，但对假手术没有影响。在表达 ENaC 的兔子解剖的集合管中，牛磺胆酸刺激净 Na + 吸收。结论 我们的结果为肝病中钠和液体潴留的新型醛固酮非依赖性机制提供了实验证据。