权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ENaC regulation by biliary factors

胆道因素对 ENaC 的调节

基本信息

批准号：
10670128
负责人：
OSSAMA B KASHLAN
金额：
$ 42.97万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10670128
关键词：
Acute Affect Alcoholic Hepatitis Aldosterone Apical Ascites Bile Acids Biliary Bilirubin Binding Binding Sites Blood Blood Volume Body Fluids Body Water Cell model Cells Charge Chemistry Chronic Colon Data Derivation procedure Distal Diuretics Drug usage Duct (organ) structure Ductal Epithelial Cell Edema Electrolytes Epithelial Cells Epithelium Excretory function Exhibits Extracellular Fluid Goals Hormonal Hyperbilirubinemia Hypertension Hypokalemia In Vitro Ion Transport Ions Kidney Learning Liddle syndrome Liquid substance Liver Liver Failure Liver diseases Measurement Measures Mediating Membrane Mineralocorticoids Modeling Molecular Mus Mutation Nephrons Patients Perfusion Peripheral Plasma Portal Hypertension Potassium Potassium Channel Regulation Renal tubule structure Renin-Angiotensin-Aldosterone System Reporting Role Sampling Serum Side Site Site-Directed Mutagenesis Sodium Spironolactone Taurocholic Acid Testing Tubular formation Urine Vasodilation Weight Xenopus oocyte absorption antagonist biophysical properties chemical property chronic liver disease driving force epithelial Na+ channel experience experimental study extracellular gain of function in vivo mutant novel therapeutics prevent response urinary

项目摘要

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.

晚期肝病患者常出现体液潴留和电解质紊乱