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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/4145

Title: PKD1 haploinsufficiency causes a syndrome of inappropriate antidiuresis in mice
Authors: Ahrabi, Ali K.
Valenti, Giovanna
Caron, Nathalie
Gal, Claudine Serradeil-Le
Raufaste, Danielle
Nielsen, Soren
Horie, Shigeo
Verbavatz, Jean-Marc
Devuyst, Olivier
Issue Date: 2007
Abstract: 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.
Notes: Univ Catholique Louvain, Sch Med, Div Nephrol, B-1200 Brussels, Belgium. Hasselt Univ, Ctr Environm Sci, Lab Cell Physiol, Diepenbeek, Belgium. Univ Bari, Dept Physiol, I-70121 Bari, Italy. Univ Mons, Dept Physiol & Pharmacol, B-7000 Mons, Belgium. Sanofi Aventis, Toulouse, France. Univ Aarhus, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Teikyo Univ, Dept Urol, Tokyo 173, Japan. CEA Saclay, Cell & Mol Imaging, F-91191 Gif Sur Yvette, France.Devuyst, O, Univ Catholique Louvain, Sch Med, Div Nephrol, 10 Ave Hippocrate, B-1200 Brussels, Belgium.devuyst@nefr.ucl.ac.be
URI: http://hdl.handle.net/1942/4145
DOI: 10.1681/ASN.2006010052
ISI #: 000246952700018
ISSN: 1046-6673
Category: A1
Type: Journal Contribution
Validation: ecoom, 2008
Appears in Collections: Research publications

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