An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells

Katharina Schrade, Jessica Tröger, Adeeb Eldahshan, Kerstin Zühlke, Kamal R. Abdul Azeez, Jonathan M. Elkins, Martin Neuenschwander, Andreas Oder, Mohamed Elkewedi, Sarah Jaksch, Karsten Andrae, Jinliang Li, Joao Fernandes, Paul Markus Müller, Stephan Grunwald, Stephen F. Marino, Tanja Vukićević, Jenny Eichhorst, Burkhard Wiesner, Marcus WeberMichael Kapiloff, Oliver Rocks, Oliver Daumke, Thomas Wieland, Stefan Knapp, Jens Peter Von Kries, Enno Klussmann

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.

Original languageEnglish (US)
Article numbere0191423
JournalPloS one
Volume13
Issue number1
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Schrade, K., Tröger, J., Eldahshan, A., Zühlke, K., Abdul Azeez, K. R., Elkins, J. M., Neuenschwander, M., Oder, A., Elkewedi, M., Jaksch, S., Andrae, K., Li, J., Fernandes, J., Müller, P. M., Grunwald, S., Marino, S. F., Vukićević, T., Eichhorst, J., Wiesner, B., ... Klussmann, E. (2018). An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells. PloS one, 13(1), [e0191423]. https://doi.org/10.1371/journal.pone.0191423