Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene

The V2 vasopressin receptor (V2R) plays a key role in the maintenance of a normal body water balance. To generate an in vivo model that allows the phy siological and molecular analysis of the role of V2Rs in kidney function, w e have created mouse lines that lack functional V2Rs by using targeted muta genesis in mouse embryonic stem cells. Specifically, we introduced a nonsen se mutation known to cause X-linked nephrogenic diabetes insipidus (XNDI) i n humans (Glu242stop) into the mouse genome. V2R-deficient hemizygous male pups showed a decrease in basal urine osmolalities and were unable to conce ntrate their urine. These pups also exhibited an enlargement of renal pelvi c space, failed to thrive, and died within the first week after birth due t o hypernatremic dehydration. Interestingly, female mice heterozygous for th e V2R mutation showed normal growth but displayed an XNDI-like phenotype, c haracterized by reduced urine concentrating ability of the kidney, polyuria , and polydipsia. Western blot analysis and immunoelectron microscopic stud ies showed that the loss of functional V2Rs had no significant effect on th e basal expression levels of aquaporin-2 and the bumetanide-sensitive Na-K- 2Cl cotransporter (BSC-1). The V2R mutant mice described here should serve as highly useful tools for the development of novel therapeutic strategies for the treatment of XNDI.