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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4090211?pdf=render |
| _version_ | 1828330875408875520 |
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| author | Jae H Sim Nathaniel J Himmel Sara K Redd Fadi E Pulous Richard T Rogers Lauren N Black Seongun M Hong Tobias N von Bergen Mitsi A Blount |
| author_facet | Jae H Sim Nathaniel J Himmel Sara K Redd Fadi E Pulous Richard T Rogers Lauren N Black Seongun M Hong Tobias N von Bergen Mitsi A Blount |
| author_sort | Jae H Sim |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-13T20:45:45Z |
| format | Article |
| id | doaj.art-def4c29090b04e37b4e08701170c4a44 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T20:45:45Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-def4c29090b04e37b4e08701170c4a442022-12-22T02:30:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0197e10175310.1371/journal.pone.0101753Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus.Jae H SimNathaniel J HimmelSara K ReddFadi E PulousRichard T RogersLauren N BlackSeongun M HongTobias N von BergenMitsi A BlountLithium, 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.http://europepmc.org/articles/PMC4090211?pdf=render |
| spellingShingle | Jae H Sim Nathaniel J Himmel Sara K Redd Fadi E Pulous Richard T Rogers Lauren N Black Seongun M Hong Tobias N von Bergen Mitsi A Blount Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC4090211?pdf=render |
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