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 similar to 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 similar to 1,000 to similar to 3,000 mosm/kg H2O, whereas the increase in Clcnk1-/- mice was only from similar to 600 to similar to 840 mosm/kg H2O, indicating nephrogenic diabetes insipidus in Clcnk1-/- mice, These results clearly established that CLC-K1 plays a major role in the urinary-concentrating mechanisms. Copyright (C) 2000 S. Karger AG, Basel.