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Nucleotides Downregulate Aquaporin 2 via Activation of Apical P2 Receptors

Scott S. P. Wildman^*, Michelle Boone, Claire M. Peppiatt-Wildman^*, Alberto Contreras-Sanz^*, Brian F. King, David G. Shirley, Peter M. T. Deen and Robert J. Unwin^,

^* Department of Veterinary Basic Sciences, Royal Veterinary College, London, United Kingdom; Centre for Nephrology, University College London Medical School, Royal Free Campus, London, United Kingdom; Department of Physiology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Research Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom

Correspondence: Dr. Scott S. P. Wildman, Urinary System Physiology Unit, Department of Veterinary Basic Sciences, Royal Veterinary College, Camden Campus, Royal College Street, London NW1 0TU, United Kingdom. Phone: +44 (0)20 7121 1903; Fax: +44 (0)20 7468 5204; E-mail: swildman{at}rvc.ac.uk

Received for publication July 7, 2008. Accepted for publication February 9, 2009.

Vasopressin regulates water reabsorption in the collecting duct, but extracellular nucleotides modulate this regulation through incompletely understood mechanisms. We investigated these mechanisms using immortalized mouse collecting duct (mpkCCD) cells. Basolateral exposure to dDAVP induced AQP2 localization to the apical membrane, but co-treatment with ATP internalized AQP2. Because plasma membrane-bound P2 receptors (P2R) mediate the effects of extracellular nucleotides, we examined the abundance and localization of P2R in mpkCCD cells. In the absence of dDAVP, P2Y₁ and P2Y₄ receptors localized to the apical membrane, whereas P2X₂, P2X₄, P2X₅, P2X₇, P2Y₂, P2Y₁₁, and P2Y₁₂ receptors localized to the cytoplasm. dDAVP induced gene expression of P2X₁, which localized to the apical domain, and led to translocation of P2X₂ and P2Y₂ to the apical and basolateral membranes, respectively. In co-expression experiments, P2R activation decreased membrane AQP2 and AQP2-mediated water permeability in Xenopus oocytes expressing P2X₂, P2Y_2, or P2Y₄ receptors, but not in oocytes expressing other P2R subtypes. In summary, these data suggest that AQP2-mediated water transport is downregulated not only by basolateral nucleotides, mediated by P2Y₂ receptors, but also by luminal nucleotides, mediated by P2X₂ and/or P2Y₄ receptors.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673