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Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice

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 (RAAS). Aldosterone dives Na(+) retention by activating the mineralocorticoid receptor and promoting the maturation and a...

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Autores principales: Wang, Xue-Ping, Mutchler, Stephanie M., Carrisoza-Gáytan, Rolando, Al-Bataineh, Mohammad, Baty, Catherine J., Vandevender, Amber, Srinivasan, Priyanka, Tan, Roderick J., Jurczak, Michael J., Satlin, Lisa M., Kashlan, Ossama B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542149/
https://www.ncbi.nlm.nih.gov/pubmed/37790468
http://dx.doi.org/10.1101/2023.09.19.558474
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author Wang, Xue-Ping
Mutchler, Stephanie M.
Carrisoza-Gáytan, Rolando
Al-Bataineh, Mohammad
Baty, Catherine J.
Vandevender, Amber
Srinivasan, Priyanka
Tan, Roderick J.
Jurczak, Michael J.
Satlin, Lisa M.
Kashlan, Ossama B.
author_facet Wang, Xue-Ping
Mutchler, Stephanie M.
Carrisoza-Gáytan, Rolando
Al-Bataineh, Mohammad
Baty, Catherine J.
Vandevender, Amber
Srinivasan, Priyanka
Tan, Roderick J.
Jurczak, Michael J.
Satlin, Lisa M.
Kashlan, Ossama B.
author_sort Wang, Xue-Ping
collection PubMed
description 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 (RAAS). Aldosterone dives Na(+) retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na(+) channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K(+)] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na(+) absorption but had no effect on K(+) secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients.
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spelling pubmed-105421492023-10-03 Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice Wang, Xue-Ping Mutchler, Stephanie M. Carrisoza-Gáytan, Rolando Al-Bataineh, Mohammad Baty, Catherine J. Vandevender, Amber Srinivasan, Priyanka Tan, Roderick J. Jurczak, Michael J. Satlin, Lisa M. Kashlan, Ossama B. bioRxiv Article 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 (RAAS). Aldosterone dives Na(+) retention by activating the mineralocorticoid receptor and promoting the maturation and apical surface expression of the epithelial Na(+) channel (ENaC), found in the aldosterone-sensitive distal nephron. However, evidence of fluid retention without RAAS activation suggests the involvement of additional mechanisms. Liver disease can greatly increase plasma and urinary bile acid concentrations and have been shown to activate ENaC in vitro. We hypothesize that elevated bile acids in liver disease activate ENaC and drive fluid retention independent of RAAS. We therefore increased circulating bile acids in mice through bile duct ligation (BDL) and measured effects on urine and body composition, while using spironolactone to antagonize the mineralocorticoid receptor. We found BDL lowered blood [K(+)] and hematocrit, and increased benzamil-sensitive natriuresis compared to sham, consistent with ENaC activation. BDL mice also gained significantly more body water. Blocking ENaC reversed fluid gains in BDL mice but had no effect in shams. In isolated collecting ducts from rabbits, taurocholic acid stimulated net Na(+) absorption but had no effect on K(+) secretion or flow-dependent ion fluxes. Our results provide experimental evidence for a novel aldosterone-independent mechanism for sodium and fluid retention in liver disease which may provide additional therapeutic options for liver disease patients. Cold Spring Harbor Laboratory 2023-09-22 /pmc/articles/PMC10542149/ /pubmed/37790468 http://dx.doi.org/10.1101/2023.09.19.558474 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Wang, Xue-Ping
Mutchler, Stephanie M.
Carrisoza-Gáytan, Rolando
Al-Bataineh, Mohammad
Baty, Catherine J.
Vandevender, Amber
Srinivasan, Priyanka
Tan, Roderick J.
Jurczak, Michael J.
Satlin, Lisa M.
Kashlan, Ossama B.
Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title_full Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title_fullStr Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title_full_unstemmed Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title_short Mineralocorticoid receptor-independent activation of ENaC in bile duct ligated mice
title_sort mineralocorticoid receptor-independent activation of enac in bile duct ligated mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542149/
https://www.ncbi.nlm.nih.gov/pubmed/37790468
http://dx.doi.org/10.1101/2023.09.19.558474
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