2. Academic Validation
  3. Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

Aurora Kinase A Is Involved in Controlling the Localization of Aquaporin-2 in Renal Principal Cells

  • Int J Mol Sci. 2022 Jan 11;23(2):763. doi: 10.3390/ijms23020763.
Sandrine Baltzer 1 2,  Timur Bulatov 2,  Christopher Schmied 3,  Andreas Krämer 4 5 6,  Benedict-Tilman Berger 4 5,  Andreas Oder 3,  Ryan Walker-Gray 1,  Christin Kuschke 1,  Kerstin Zühlke 1,  Jenny Eichhorst 3,  Martin Lehmann 3,  Stefan Knapp 4 5 6 7,  John Weston 8,  Jens Peter von Kries 3,  Roderich D Süssmuth 2,  Enno Klussmann 1 9
Affiliations

Affiliations

  • 1 Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
  • 2 Institute of Chemistry, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany.
  • 3 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
  • 4 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
  • 5 Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany.
  • 6 DKTK (German Translational Research Network), Partner Site Frankfurt/Mainz, 60590 Frankfurt am Main, Germany.
  • 7 Frankfurt Cancer Institute, 60596 Frankfurt am Main, Germany.
  • 8 JQuest Consulting, Carl-Orff-Weg 25, 65779 Kelkheim, Germany.
  • 9 DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10785 Berlin, Germany.
PMID: 35054947 DOI: 10.3390/ijms23020763
Abstract

The cAMP-dependent aquaporin-2 (AQP2) redistribution from intracellular vesicles into the plasma membrane of renal collecting duct principal cells induces water reabsorption and fine-tunes body water homeostasis. However, the mechanisms controlling the localization of AQP2 are not understood in detail. Using immortalized mouse medullary collecting duct (MCD4) and primary rat inner medullary collecting duct (IMCD) cells as model systems, we here discovered a key regulatory role of Aurora Kinase A (AURKA) in the control of AQP2. The AURKA-selective inhibitor Aurora-A inhibitor I and novel derivatives as well as a structurally different inhibitor, Alisertib, prevented the cAMP-induced redistribution of AQP2. Aurora-A inhibitor I led to a depolymerization of actin stress fibers, which serve as tracks for the translocation of AQP2-bearing vesicles to the plasma membrane. The phosphorylation of cofilin-1 (CFL1) inactivates the actin-depolymerizing function of CFL1. Aurora-A inhibitor I decreased the CFL1 phosphorylation, accounting for the removal of the actin stress fibers and the inhibition of the redistribution of AQP2. Surprisingly, Alisertib caused an increase in actin stress fibers and did not affect CFL1 phosphorylation, indicating that AURKA exerts its control over AQP2 through different mechanisms. An involvement of AURKA and CFL1 in the control of the localization of AQP2 was hitherto unknown.

Keywords

AQP2; AURKA; AVP; actin cytoskeleton; cofilin-1.

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