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Gain-of-function mutations of the V2 vasopressin receptor in nephrogenic syndrome of inappropriate antidiuresis (NSIAD): a cell-based assay to assess constitutive water reabsorption

  • Marianna Ranieri
  • Grazia Tamma
  • Tommaso Pellegrino
  • Vanessa Vezzi
  • Caterina Ambrosio
  • Cristina Grò
  • Annarita Di Mise
  • Tommaso Costa
  • Giovanna ValentiEmail author
  • Susanna CotecchiaEmail author
Molecular and cellular mechanisms of disease
Part of the following topical collections:
  1. Molecular and cellular mechanisms of disease

Abstract

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently identified chromosome X-linked disease associated with gain-of-function mutations of the V2 vasopressin receptor (V2R), a G-protein-coupled receptor. It is characterized by inability to excrete a free water load, hyponatremia, and undetectable vasopressin-circulating levels. Hyponatremia can be quite severe in affected male children. To gain a deeper insight into the functional properties of the V2R active mutants and how they might translate into the pathological outcome of NSIAD, in this study, we have expressed the wild-type V2R and three constitutively active V2R mutants associated with NSIAD (R137L, R137C, and the F229V) in MCD4 cells, a cell line derived from renal mouse collecting duct, stably expressing the vasopressin-sensitive water channel aquaporin-2 (AQP2). Our findings indicate that in cells expressing each active mutant, AQP2 was constitutively localized to the apical plasma membrane in the absence of vasopressin stimulation. In line with these observations, under basal conditions, osmotic water permeability in cells expressing the constitutively active mutants was significantly higher compared to that of cells expressing the wild-type V2R. Our findings demonstrate a direct link between activating mutations of the V2R and the perturbation of water balance in NSIAD. In addition, this study provides a useful cell-based assay system to assess the functional consequences of newly discovered activating mutations of the V2R on water permeability in kidney cells and to screen the effect of drugs on the mutated receptors.

Keywords

V2 receptor AQP2 NSIAD 

Notes

Acknowledgments

We are grateful to Dr. Paola Molinari (Istituto Superiore di Sanità, Rome) for her advice in signal transduction experiments and Prof. Francesca Fanelli (University of Modena-Reggio Emilia) for helpful discussions. We thank Prof. Michel Bouvier (University of Montreal, Canada) for providing the cDNA of the V2 receptors.

Funding information

The financial support of Telethon - Italy (Grant Number GGP13227) is gratefully acknowledged. Marianna Ranieri is a postdoctoral research fellow supported by “Intervento cofinanziato dal Fondo di Sviluppo e Coesione 2007-2013–APQ Ricerca Regione Puglia, Programma Regionale a Sostegno della Specializzazione Intelligente e della Sostenibilità Sociale ed Ambientale–FutureInResearch.”

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Marianna Ranieri
    • 1
  • Grazia Tamma
    • 1
    • 2
  • Tommaso Pellegrino
    • 1
  • Vanessa Vezzi
    • 3
  • Caterina Ambrosio
    • 3
  • Cristina Grò
    • 3
  • Annarita Di Mise
    • 1
  • Tommaso Costa
    • 3
  • Giovanna Valenti
    • 1
    • 2
    • 4
    Email author
  • Susanna Cotecchia
    • 1
    Email author
  1. 1.Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of BariBariItaly
  2. 2.Istituto Nazionale di Biostrutture e BiosistemiRomeItaly
  3. 3.Department of PharmacologyIstituto Superiore di SanitàRomeItaly
  4. 4.Center of Excellence in Comparative Genomics (CEGBA)University of BariBariItaly

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