Severely impaired urine-concentrating ability in mice lacking the CLC-K1 chloride channel.

To analyze the physiological functions of CLC-K1 in vivo, we generated mice lacking CLC-K1 by targeted gene disruption. Homozygous mutant Clcnk1-/- mice produced approximately 5 times more urine than Clcnk1+/- and Clcnk1+/+ mice. After 24-hour water deprivation, Clcnk1-/- mice became severely dehydrated and lethargic. Intraperitoneal injection of the V2 agonist, deamino-Cys(1), D-Arg(8) vasopressin, induced an increase in urine osmolarity in Clcnk1+/- and Clcnk1+/+ mice from approximately 1,000 to approximately 3,000 mosm/kg H(2)O, whereas the increase in Clcnk1-/- mice was only from approximately 600 to approximately 840 mosm/kg H(2)O, indicating nephrogenic diabetes insipidus in Clcnk1-/- mice. These results clearly established that CLC-K1 plays a major role in the urinary-concentrating mechanisms.