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1 Internal Medicine/Renal Division, Washington University School of Medicine, St. Louis, Missouri, United States
2 Internal Medicine/Renal Division, Washington University School of Medicine, St. Louis, Missouri, United States; Cell biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States
3 Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri, United States
4 Department of Pathology, University of California-San Diego, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: fchen{at}im.wustl.edu.
The aquaporin 2 (AQP2) channel mediates the reabsorption of water in renal collecting ducts in response to arginine vasopressin (AVP) and hypertonicity. Here we show that AQP2 expression was induced not only by the TonEBP/NFAT5-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.
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