Calcineurin-NFATc signaling pathway regulates AQP2 expression in response to calcium signals and osmotic stress

Am J Physiol Cell Physiol. 2007 May;292(5):C1606-16. doi: 10.1152/ajpcell.00588.2005. Epub 2006 Dec 13.


The aquaporin (AQP)2 channel mediates the reabsorption of water in renal collecting ducts in response to arginine vasopressin (AVP) and hypertonicity. Here we show that AQP2 expression is induced not only by the tonicity-responsive enhancer binding protein (TonEBP)/nuclear factor of activated T cells (NFAT)5-mediated hypertonic stress response but also by the calcium-dependent calcineurin-NFATc pathway. The induction of AQP2 expression by the calcineurin-NFATc pathway can occur in the absence of TonEBP/NFAT5. Mutational and chromatin immunoprecipitation analyses revealed the existence of functional NFAT binding sites within the proximal AQP2 promoter responsible for regulation of AQP2 by NFATc proteins and TonEBP/NFAT5. Contrary to the notion that TonEBP/NFAT5 is the only Rel/NFAT family member regulated by tonicity, we found that hypertonicity promotes the nuclear translocation of NFATc proteins for the subsequent induction of AQP2 expression. Calcineurin activity was also found to be involved in the induction of TonEBP/NFAT5 expression by hypertonicity, thus further defining the signaling mechanisms that underlie the TonEBP/NFAT5 osmotic stress response pathway. The coordinate regulation of AQP2 expression by both osmotic stress and calcium signaling appears to provide a means to integrate diverse extracellular signals into optimal cellular responses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Aquaporin 2 / genetics
  • Aquaporin 2 / metabolism*
  • Calcineurin / metabolism*
  • Calcium Signaling
  • Cell Line
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / metabolism*
  • Kidney Tubules, Collecting / physiopathology
  • Mice
  • Mice, Knockout
  • Mutation
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Osmosis
  • Promoter Regions, Genetic
  • Saline Solution, Hypertonic / pharmacology
  • Signal Transduction* / drug effects
  • Stress, Physiological / metabolism*
  • Stress, Physiological / physiopathology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Up-Regulation
  • Water-Electrolyte Balance


  • Aqp2 protein, mouse
  • Aquaporin 2
  • Ionophores
  • NFATC Transcription Factors
  • Nfat5 protein, mouse
  • Nfatc1 protein, mouse
  • Saline Solution, Hypertonic
  • Transcription Factors
  • Ionomycin
  • Calcineurin
  • Tetradecanoylphorbol Acetate