Received January 18, 2006
Accepted on March 9, 2007

BASIC SCIENCE ARTICLES: Pathophysiology of Renal Disease and Progression

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 ^*1

*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

¹ To whom correspondence should be addressed. E-mail: devuyst{at}nefr.ucl.ac.be.

	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.