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Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel
- Source :
- Nature Genetics. 21:95-98
- Publication Year :
- 1999
- Publisher :
- Springer Science and Business Media LLC, 1999.
-
Abstract
- CLC-K1 is a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) in the inner medulla 1, 2 . Transport of NaCl in the tAL is thought to be a component of urinary concentration in a passive model of the countercurrent multiplication system 3, 4, 5 , but there has been no direct evidence that CLC-K1 is involved in urine concentration. To analyse the physiological function of CLC-K1 in vivo , we generated mice lacking CLC-K1 by targeted gene disruption. Clcnk1 –/– mice were physically normal appearance, but produced approximately five times more urine than Clcnk1 +/– and Clcnk1 +/+ mice. After 24 hours of water deprivation, Clcnk1 –/– mice were severely dehydrated and lethargic, with a decrease of approximately 27% in body weight. Intraperitoneal injection of the V2 agonist 1-deamino-8-D-arginine vasopressin (dDAVP) induced a threefold increase in urine osmolarity in Clcnk1 +/– and Clcnk1 +/+ mice, whereas only a minimal increase was seen in Clcnk1 –/– mice, indicating nephrogenic diabetes insipidus. After in vitro perfusion of the tAL, the lumen-to-bath chloride gradient did not produce a diffusion potential in Clcnk1 –/– mice in contrast to Clcnk1 +/+ and Clcnk1 +/– mice. These results establish that CLC-K1 has a role in urine concentration, and that the countercurrent system in the inner medulla is involved in the generation and maintenance of hypertonic medullary interstitium.
- Subjects :
- medicine.medical_specialty
Vasopressin
urogenital system
Countercurrent multiplication
Biology
Medullary interstitium
medicine.disease
Nephrogenic diabetes insipidus
Transepithelial chloride transport
Endocrinology
Internal medicine
Diabetes insipidus
Genetics
Chloride channel
medicine
Urine osmolality
Subjects
Details
- ISSN :
- 15461718 and 10614036
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Nature Genetics
- Accession number :
- edsair.doi...........b80f65b0ccc7dfc917eb6464218a1897