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This Article Full Text Full Text (PDF) Data Supplement Data Supplement All Versions of this Article: ASN.2006010052v1 18/6/1740    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ahrabi, A. K. Articles by Devuyst, O. Search for Related Content PubMed PubMed Citation Articles by Ahrabi, A. K. Articles by Devuyst, O.

PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice

Ali K. Ahrabi^*, Sara Terryn, Giovanna Valenti, Nathalie Caron, Claudine Serradeil-Le Gal^||, Danielle Raufaste^||, Soren Nielsen^¶, Shigeo Horie^**, Jean-Marc Verbavatz and Olivier Devuyst^*

^* Division of Nephrology, Université catholique de Louvain Medical School, Brussels, Belgium; Laboratory of Cell Physiology, Center for Environmental Sciences, Hasselt University, Diepenbeek, Belgium; Department of Physiology, University of Bari, Bari, Italy; Department of Physiology and Pharmacology, University of Mons-Hainaut, Mons, Belgium; ^|| Sanofi-Aventis, Toulouse, France; ^¶ The Water and Salt Research Center, University of Aarhus, Aarhus, Denmark; ^** Department of Urology, Teikyo University, Tokyo, Japan; and Cell and Molecular Imaging, CEA/Saclay, Gif-sur-Yvette, France

Address correspondence to: Dr. Olivier Devuyst, Division of Nephrology, UCL Medical School, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: +32-2-764-5450; Fax: +32-2-764-5455; E-mail: devuyst{at}nefr.ucl.ac.be

Received for publication January 18, 2006. Accepted for publication March 9, 2007.

Mutations in PKD1 are associated with autosomal dominant polycystic kidney disease. Studies in mouse models suggest that the vasopressin (AVP) V2 receptor (V2R) pathway is involved in renal cyst progression, but potential changes before cystogenesis are unknown. This study used a noncystic mouse model to investigate the effect of Pkd1 haploinsufficiency on water handling and AVP signaling in the collecting duct (CD). In comparison with wild-type littermates, Pkd1^+/– mice showed inappropriate antidiuresis with higher urine osmolality and lower plasma osmolality at baseline, despite similar renal function and water intake. The Pkd1^+/– mice had a decreased aquaretic response to both a water load and a selective V2R antagonist, despite similar V2R distribution and affinity. They showed an inappropriate expression of AVP in brain, irrespective of the hypo-osmolality. The cAMP levels in kidney and urine were unchanged, as were the mRNA levels of aquaporin-2 (AQP2), V2R, and cAMP-dependent mediators in kidney. However, the (Ser256) phosphorylated AQP2 was upregulated in Pkd1^+/– kidneys, with AQP2 recruitment to the apical plasma membrane of CD principal cells. The basal intracellular Ca²⁺ concentration was significantly lower in isolated Pkd1^+/– CD, with downregulated phosphorylated extracellular signal–regulated kinase 1/2 and decreased RhoA activity. Thus, in absence of cystic changes, reduced Pkd1 gene dosage is associated with a syndrome of inappropriate antidiuresis (positive water balance) reflecting decreased intracellular Ca²⁺ concentration, decreased activity of RhoA, recruitment of AQP2 in the CD, and inappropriate expression of AVP in the brain. These data give new insights in the potential roles of polycystin-1 in the AVP and Ca²⁺ signaling and the trafficking of AQP2 in the CD.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673