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Abstract: FR-PO623

Functional Characterization of Gain-of-Function Mutations of the V2 Vasopressin Receptor Leading to Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD)

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic


  • Ranieri, Marianna, University of Bari, Bari, Italy
  • Tamma, Grazia, University of Bari, Bari, Italy
  • Vezzi, Vanessa, Istituto Superiore di Sanità, Rome, Italy
  • Di Mise, Annarita, University of Bari, Bari, Italy
  • Venneri, Maria, University of Bari, Bari, Italy
  • Centrone, Mariangela, University of Bari, Bari, Italy
  • Cotecchia, Susanna, University of Bari, Bari, Italy
  • Valenti, Giovanna, University of Bari, Bari, Italy

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a chromosome X-linked disease associated to gain-of-function mutations of the V2 vasopressin receptor (V2R), a G protein-coupled receptor. NSIAD can be quite severe in affected male children. It is characterized by inability to excrete a free water load, hyponatremia, and undetectable vasopressin circulating levels.


In this study, we have expressed the wild type V2R and three constitutively active V2R mutants, the 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).


In cells expressing each active mutant, AQP2 was constitutively localized to the apical plasma membrane, in the absence of vasopressin stimulation. Conversely, in cells expressing the wild type V2R, AQP2 was localized in intracellular vesicles and redistributed to the apical membrane in response to vasopressin. In line with these observations, under basal conditions, osmotic water permeability of each constitutively active mutant was significantly higher compared with that of cells expressing the wild type V2R. Interestingly, specific inhibition of PKA reduced the basal osmotic water permeability only in F229V expressing cells, indicating the activation of a PKA-dependent pathway. Conversely, for the R137L and R137C mutants a PKA-independent signalling leading to redistribution of AQP2 and consequent increase in osmotic water permeability is predicted.


Our findings demonstrate, for the first time, a direct link between the activating mutations of the V2R and the alteration of water permeability in cells expressing V2R mutants providing a rationale for the water balance disturbance observed in NSIAD.


  • Government Support - Non-U.S.