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Abstract: TH-PO344

Tamoxifen Affects Regulation and Localization of AQP3 and AQP4 in Response to Lithium-Induced Nephrogenic Diabetes Insipidus and Unilateral Ureteral Obstruction in Rats

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic

Authors

  • Tingskov, Stine Julie, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • D'Agostino, Mariagrazia, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Login, Frédéric H., Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Nejsum, Lene N., Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Norregaard, Rikke, Aarhus Universitet, Aarhus, Midtjylland, Denmark

Group or Team Name

  • The Nørregaard Lab
Background

Estrogen is known to play a role in the regulation of water homeostasis, and it has been shown that estrogen affects AQP2 expression. Previously, we have demonstrated that the selective estrogen receptor modulator, tamoxifen (TAM) regulates AQP2 in different animal models, namely the lithium-induced nephrogenic diabetes insipidus (NDI) model and the unilateral ureteral obstruction (UUO) CKD model. AQP3 and AQP4 are also affected in response to NDI and UUO. However, it is not known whether TAM influences AQP3 and AQP4 levels and cellular localization.

Methods

In the first model rats were treated for 14 days with lithium to induce NDI and TAM treatment (25 and 50 mg/kg by oral gavage) was initiated one week after onset of lithium administration. For the second model rats were subjected to 7 days of UUO. Tamoxifen (50 mg/kg) was given 5 days before the operation and was continued for 7 days after UUO. Levels and cellular localization of AQP3 and AQP4 were evaluated by immunohistochemistry and western blot analysis. To study the intracellular localization and trafficking of AQP3, Madin-Darby Canine Kidney (MDCK) cells stably expressing AQP3 (AQP3-EGFP) were treated with either LiCl or TGF-β alone or combined toTAM.

Results

Western blot analysis showed that lithium treatment decreased AQP3 total protein levels, which was not significantly affected by TAM. However, TAM affects AQP3 localization to be more lateral in lithium-treated rats. After UUO, AQP3 and AQP4 protein levels were reduced, which was attenuated by TAM. Immunohistochemistry analysis confirmed these results. In AQP3-MDCK cells, AQP3 localized mainly within the cytoplasm after LiCl and TGF-β treatment. In the presence of TAM, AQP3 seems to relocalize into the plasma membrane.

Conclusion

These findings indicate that TAM affects the localization of AQP3 in Li-exposed rats and MDCK cells. TAM also prevents downregulation of inner medullary AQP3 and AQP4 in UUO rats. Therefore, TAM might have a therapeutic potential in obstruction-associated dysregulation of fluid metabolisms.