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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.00948

Vasopressin-independent regulation of aquaporin-2 by tamoxifen in kidney collecting ducts

 Stine Julie Tingskov1, Hyo-Jung Choi2,  Mikkel R. Holst3,  Shan Hu4, Chunling Li4,  Weidong Wang4, Jørgen Frøkiær3, Lene N. Nejsum3,  Tae-Hwan Kwon2* and  Rikke Norregaard1*
  • 1Department of Clinical Medicine, Aarhus University, Denmark
  • 2Department of Microbiology, Kyungpook National University School of Medicine, South Korea
  • 3Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark
  • 4Zhongshan School of Medicine, Sun Yat-sen University, China

Arginine vasopressin (AVP) mediates water reabsorption in the kidney collecting ducts through regulation of aquaporin-2 (AQP2). Also, estrogen has been known to regulate AQP2. Consistently, we previously demonstrated that tamoxifen (TAM), a selective estrogen receptor modulator, attenuates the downregulation of AQP2 in lithium-induced nephrogenic diabetes insipidus (NDI). In this study, we investigated the AVP-independent regulation of AQP2 by TAM and the therapeutic effect of TAM on the dysregulation of AQP2 and impaired urinary concentration in a unilateral ureteral obstruction (UUO) model.
Primary cultured inner medullary collecting duct (IMCD) cells from kidneys of male Sprague-Dawley rats were treated with TAM. Rats subjected to 7 days UUO were treated with TAM by oral gavage. Changes of intracellular trafficking and expression of AQP2 were evaluated by quantitative PCR, western blotting and immunohistochemistry.
TAM induced AQP2 protein expression and intracellular trafficking in primary cultured IMCD cells, which were independent of the vasopressin V2 receptor (V2R) and cAMP activation; the critical pathways involved in AVP-stimulated regulation of AQP2. TAM attenuated the downregulation of AQP2 in TGF-β treated IMCD cells and IMCD suspensions pre-pared from UUO rats. TAM administration in vivo attenuated the downregulation of AQP2, associated with an improvement of urinary concentration in UUO rats. In addition, TAM in-creased CaMKII expression, suggesting that calmodulin signaling pathway is likely to be involved in the TAM-mediated AQP2 regulation.
In conclusion, TAM is involved in AQP2 regulation in a vasopressin-independent manner and improves urinary concentration by attenuating the down-regulation of AQP2 and maintaining intracellular trafficking in UUO.

Keywords: AQP2, IMCD, Tamoxifen (TAM), unilateral ureter obstruction, vasopressin

Received: 20 May 2019; Accepted: 09 Jul 2019.

Edited by:

Alexander Staruschenko, Medical College of Wisconsin, United States

Reviewed by:

Janet D. Klein, Emory University, United States
Zhanjun Jia, Nanjing Medical University, China  

Copyright: © 2019 Tingskov, Choi, Holst, Hu, Li, Wang, Frøkiær, Nejsum, Kwon and Norregaard. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Tae-Hwan Kwon, Department of Microbiology, Kyungpook National University School of Medicine, Daegu, South Korea, thkwon@knu.ac.kr
Dr. Rikke Norregaard, Aarhus University, Department of Clinical Medicine, Aarhus, 8000, Central Denmark Region, Denmark, rikke.norregaard@ki.au.dk