Severely Impaired Urine-Concentrating Ability in Mice Lacking the CLC-K1 Chloride Channel
| Title: | Severely Impaired Urine-Concentrating Ability in Mice Lacking the CLC-K1 Chloride Channel |
|---|---|
| Authors: | Uchida, Shinichi; Marumo, MD, Fumiaki |
| Publisher: | Experimental Nephrology |
| Date Published: | November 2000 - December 2000 |
| Reference Number: | 512 |
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. Copyright 2000 S. Karger AG, Basel
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
These researchers sought to discover what physiological role CLC-K1 plays in the physiology. They had previously determined that CLC-K1 was located exclusively in the interior of the kidney, especially in the thin ascending portion of Henle's Loop (tAL). CLC-K1 is highly permeable to chloride, and the authors determined that it is a major chloride channel responsible for the high chloride permeability in the tAL. They hypothesized that CLC-K1 plays an important role in enabling the kidney to concentrate urine.
To test their hypothesis, the authors generated a line of mice that lacked the CLC-K1 gene and thus could not generate any CLC-K1. They observed this line of mice and compared them to control groups. They found mice lacking CLC-K1s produced five times more urine that the controls. These mice also became severely dehydrated and lethargic when deprived of water for 24 hours. They also did not produce a significant increase in urine concentration when injected with vasopressin immediately after the period of water deprivation.
These are all indications of nephrogenic diabetes insipidus (NDI), which is a severe inability to concentrate urine. Thus, the results showed that CLC-K1 plays a major role in the kidney's ability to concentrate urine. These findings also suggest that mutations of the CLC-K1 gene in humans may be associated with NDI. However, there has been no report of a mutated CLC-K1 in an NDI patient. Perhaps, due to physiologic differences, the urine concentrating defect resulting from a lack of CLC-K1s is less severe in humans than mice.