Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus
Lithium is widely used in the treatment of bipolar affective disorders, but often causes nephrogenic diabetes insipidus (NDI), a condition characterized by a severe urinary concentrating defect. Lithium-induced NDI is associated with dysregulation of the amiloride-sensitive epithelial sodium channel...
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doaj-2dca7fadff884e88bdc697f72270ae0d2020-11-24T22:37:37ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2018-07-01910.3389/fphys.2018.00903385382Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes InsipidusStine Julie Tingskov0Tae-Hwan Kwon1Jørgen Frøkiær2Rikke Nørregaard3Department of Clinical Medicine, Aarhus University, Aarhus, DenmarkDepartment of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, South KoreaDepartment of Clinical Medicine, Aarhus University, Aarhus, DenmarkDepartment of Clinical Medicine, Aarhus University, Aarhus, DenmarkLithium is widely used in the treatment of bipolar affective disorders, but often causes nephrogenic diabetes insipidus (NDI), a condition characterized by a severe urinary concentrating defect. Lithium-induced NDI is associated with dysregulation of the amiloride-sensitive epithelial sodium channel (ENaC), which is essential for renal sodium reabsorption. Sex hormones have been shown to affect the expression of aquaporin-2 (AQP2) and sodium transporters. Therefore, we evaluated whether tamoxifen (TAM), a selective estrogen receptor modulator (SERM), would affect lithium-induced dysregulation of ENaC subunits and natriuresis. Rats were fed with lithium-containing food for 2 weeks to induce NDI and natriuresis. TAM was administered daily via gastric gavage after 1 week of lithium administration. Lithium treatment alone resulted in increased urinary sodium excretion and significant reduction of βENaC and γENaC at both RNA and protein levels. In addition, the plasma sodium level reduced after lithium treatment. Administration of TAM prevented increased urinary sodium excretion as well as attenuated the downregulation of βENaC and γENaC. Consistent with these findings, immunohistochemistry (IHC) showed stronger labeling of βENaC and γENaC subunits in the apical domain of the collecting duct cells in the cortical tissue of lithium-fed rats treated with TAM. Other major sodium transporters including NaPi-2, NKCC2, Na/K-ATPase, and NHE3, are believed not to have an effect on the increased urinary sodium excretion since their expression increased or was unchanged after treatment with lithium. In conclusion, the results demonstrated that TAM rescued the adverse effects of the lithium-induced increase in fractional excretion of sodium after the establishment of lithium-induced NDI.https://www.frontiersin.org/article/10.3389/fphys.2018.00903/fulltamoxifenlithiumnatriuresisENaCsodium transporter |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Stine Julie Tingskov Tae-Hwan Kwon Jørgen Frøkiær Rikke Nørregaard |
spellingShingle |
Stine Julie Tingskov Tae-Hwan Kwon Jørgen Frøkiær Rikke Nørregaard Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus Frontiers in Physiology tamoxifen lithium natriuresis ENaC sodium transporter |
author_facet |
Stine Julie Tingskov Tae-Hwan Kwon Jørgen Frøkiær Rikke Nørregaard |
author_sort |
Stine Julie Tingskov |
title |
Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus |
title_short |
Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus |
title_full |
Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus |
title_fullStr |
Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus |
title_full_unstemmed |
Tamoxifen Decreases Lithium-Induced Natriuresis in Rats With Nephrogenic Diabetes Insipidus |
title_sort |
tamoxifen decreases lithium-induced natriuresis in rats with nephrogenic diabetes insipidus |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2018-07-01 |
description |
Lithium is widely used in the treatment of bipolar affective disorders, but often causes nephrogenic diabetes insipidus (NDI), a condition characterized by a severe urinary concentrating defect. Lithium-induced NDI is associated with dysregulation of the amiloride-sensitive epithelial sodium channel (ENaC), which is essential for renal sodium reabsorption. Sex hormones have been shown to affect the expression of aquaporin-2 (AQP2) and sodium transporters. Therefore, we evaluated whether tamoxifen (TAM), a selective estrogen receptor modulator (SERM), would affect lithium-induced dysregulation of ENaC subunits and natriuresis. Rats were fed with lithium-containing food for 2 weeks to induce NDI and natriuresis. TAM was administered daily via gastric gavage after 1 week of lithium administration. Lithium treatment alone resulted in increased urinary sodium excretion and significant reduction of βENaC and γENaC at both RNA and protein levels. In addition, the plasma sodium level reduced after lithium treatment. Administration of TAM prevented increased urinary sodium excretion as well as attenuated the downregulation of βENaC and γENaC. Consistent with these findings, immunohistochemistry (IHC) showed stronger labeling of βENaC and γENaC subunits in the apical domain of the collecting duct cells in the cortical tissue of lithium-fed rats treated with TAM. Other major sodium transporters including NaPi-2, NKCC2, Na/K-ATPase, and NHE3, are believed not to have an effect on the increased urinary sodium excretion since their expression increased or was unchanged after treatment with lithium. In conclusion, the results demonstrated that TAM rescued the adverse effects of the lithium-induced increase in fractional excretion of sodium after the establishment of lithium-induced NDI. |
topic |
tamoxifen lithium natriuresis ENaC sodium transporter |
url |
https://www.frontiersin.org/article/10.3389/fphys.2018.00903/full |
work_keys_str_mv |
AT stinejulietingskov tamoxifendecreaseslithiuminducednatriuresisinratswithnephrogenicdiabetesinsipidus AT taehwankwon tamoxifendecreaseslithiuminducednatriuresisinratswithnephrogenicdiabetesinsipidus AT jørgenfrøkiær tamoxifendecreaseslithiuminducednatriuresisinratswithnephrogenicdiabetesinsipidus AT rikkenørregaard tamoxifendecreaseslithiuminducednatriuresisinratswithnephrogenicdiabetesinsipidus |
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