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Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus

Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the...

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Autores principales: Sim, Jae H., Himmel, Nathaniel J., Redd, Sara K., Pulous, Fadi E., Rogers, Richard T., Black, Lauren N., Hong, Seongun M., von Bergen, Tobias N., Blount, Mitsi A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090211/
https://www.ncbi.nlm.nih.gov/pubmed/25006961
http://dx.doi.org/10.1371/journal.pone.0101753
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author Sim, Jae H.
Himmel, Nathaniel J.
Redd, Sara K.
Pulous, Fadi E.
Rogers, Richard T.
Black, Lauren N.
Hong, Seongun M.
von Bergen, Tobias N.
Blount, Mitsi A.
author_facet Sim, Jae H.
Himmel, Nathaniel J.
Redd, Sara K.
Pulous, Fadi E.
Rogers, Richard T.
Black, Lauren N.
Hong, Seongun M.
von Bergen, Tobias N.
Blount, Mitsi A.
author_sort Sim, Jae H.
collection PubMed
description Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.
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spelling pubmed-40902112014-07-14 Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus Sim, Jae H. Himmel, Nathaniel J. Redd, Sara K. Pulous, Fadi E. Rogers, Richard T. Black, Lauren N. Hong, Seongun M. von Bergen, Tobias N. Blount, Mitsi A. PLoS One Research Article Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in ∼40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCα KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCα KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCα KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCα KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCα KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCα KO mice. Our data show that ablation of PKCα preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy. Public Library of Science 2014-07-09 /pmc/articles/PMC4090211/ /pubmed/25006961 http://dx.doi.org/10.1371/journal.pone.0101753 Text en © 2014 Sim et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sim, Jae H.
Himmel, Nathaniel J.
Redd, Sara K.
Pulous, Fadi E.
Rogers, Richard T.
Black, Lauren N.
Hong, Seongun M.
von Bergen, Tobias N.
Blount, Mitsi A.
Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title_full Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title_fullStr Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title_full_unstemmed Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title_short Absence of PKC-Alpha Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
title_sort absence of pkc-alpha attenuates lithium-induced nephrogenic diabetes insipidus
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090211/
https://www.ncbi.nlm.nih.gov/pubmed/25006961
http://dx.doi.org/10.1371/journal.pone.0101753
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