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Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms

Lithium chloride (LiCl) is a widely used drug for the treatment of bipolar disorders, but as a side effect, 40% of the patients develop diabetes insipidus. LiCl affects the activity of the glycogen synthase kinase 3 (GSK3), and mice deficient for GSK3β showed a reduction in the urine concentration c...

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Autores principales: Kaiser, Marc, Edemir, Bayram
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226097/
https://www.ncbi.nlm.nih.gov/pubmed/32340354
http://dx.doi.org/10.3390/cells9041060
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author Kaiser, Marc
Edemir, Bayram
author_facet Kaiser, Marc
Edemir, Bayram
author_sort Kaiser, Marc
collection PubMed
description Lithium chloride (LiCl) is a widely used drug for the treatment of bipolar disorders, but as a side effect, 40% of the patients develop diabetes insipidus. LiCl affects the activity of the glycogen synthase kinase 3 (GSK3), and mice deficient for GSK3β showed a reduction in the urine concentration capability. The cellular and molecular mechanisms are not fully understood. We used primary cultured inner medullary collecting duct cells to analyze the underlying mechanisms. LiCl and the inhibitor of GSK3 (SB216763) induced a decrease in the aquaporin-2 (Aqp2) protein level. LiCl induced downregulation of Aqp2 mRNA expression while SB216763 had no effect and TWS119 led to increase in expression. The inhibition of the lysosomal activity with bafilomycin or chloroquine prevented both LiCl- and SB216763-mediated downregulation of Aqp2 protein expression. Bafilomycin and chloroquine induced the accumulation of Aqp2 in lysosomal structures, which was prevented in cells treated with dibutyryl cyclic adenosine monophosphate (dbcAMP), which led to phosphorylation and membrane localization of Aqp2. Downregulation of Aqp2 was also evident when LiCl was applied together with dbcAMP, and dbcAMP prevented the SB216763-induced downregulation. We showed that LiCl and SB216763 induce downregulation of Aqp2 via different mechanisms. While LiCl also affected the mRNA level, SB216763 induced lysosmal degradation. Specific GSK3β inhibition had an opposite effect, indicating a more complex regulatory mechanism.
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spelling pubmed-72260972020-05-18 Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms Kaiser, Marc Edemir, Bayram Cells Article Lithium chloride (LiCl) is a widely used drug for the treatment of bipolar disorders, but as a side effect, 40% of the patients develop diabetes insipidus. LiCl affects the activity of the glycogen synthase kinase 3 (GSK3), and mice deficient for GSK3β showed a reduction in the urine concentration capability. The cellular and molecular mechanisms are not fully understood. We used primary cultured inner medullary collecting duct cells to analyze the underlying mechanisms. LiCl and the inhibitor of GSK3 (SB216763) induced a decrease in the aquaporin-2 (Aqp2) protein level. LiCl induced downregulation of Aqp2 mRNA expression while SB216763 had no effect and TWS119 led to increase in expression. The inhibition of the lysosomal activity with bafilomycin or chloroquine prevented both LiCl- and SB216763-mediated downregulation of Aqp2 protein expression. Bafilomycin and chloroquine induced the accumulation of Aqp2 in lysosomal structures, which was prevented in cells treated with dibutyryl cyclic adenosine monophosphate (dbcAMP), which led to phosphorylation and membrane localization of Aqp2. Downregulation of Aqp2 was also evident when LiCl was applied together with dbcAMP, and dbcAMP prevented the SB216763-induced downregulation. We showed that LiCl and SB216763 induce downregulation of Aqp2 via different mechanisms. While LiCl also affected the mRNA level, SB216763 induced lysosmal degradation. Specific GSK3β inhibition had an opposite effect, indicating a more complex regulatory mechanism. MDPI 2020-04-23 /pmc/articles/PMC7226097/ /pubmed/32340354 http://dx.doi.org/10.3390/cells9041060 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kaiser, Marc
Edemir, Bayram
Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title_full Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title_fullStr Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title_full_unstemmed Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title_short Lithium Chloride and GSK3 Inhibition Reduce Aquaporin-2 Expression in Primary Cultured Inner Medullary Collecting Duct Cells Due to Independent Mechanisms
title_sort lithium chloride and gsk3 inhibition reduce aquaporin-2 expression in primary cultured inner medullary collecting duct cells due to independent mechanisms
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226097/
https://www.ncbi.nlm.nih.gov/pubmed/32340354
http://dx.doi.org/10.3390/cells9041060
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AT edemirbayram lithiumchlorideandgsk3inhibitionreduceaquaporin2expressioninprimaryculturedinnermedullarycollectingductcellsduetoindependentmechanisms