Grill, A. and Schiessl, I. M. and Gess, B. and Fremter, K. and Hammer, A. and Castrop, H. (2016) Salt-losing nephropathy in mice with a null mutation of the Clcnk2 gene. ACTA PHYSIOLOGICA, 218 (3). pp. 198-211. ISSN 1748-1708, 1748-1716
Full text not available from this repository. (Request a copy)Abstract
AimThe basolateral chloride channel ClC-Kb facilitates Cl reabsorption in the distal nephron of the human kidney. Functional mutations in CLCNKB are associated with Bartter's syndrome type 3, a hereditary salt-losing nephropathy. To address the function of ClC-K2 invivo, we generated ClC-K2-deficient mice. MethodsClC-K2-deficient mice were generated using TALEN technology. ResultsClC-K2-deficient mice were viable and born in a Mendelian ratio. ClC-K2-/- mice showed no gross anatomical abnormalities, but they were growth retarded. The 24-h urine volume was increased in ClC-K2-/- mice (4.40.6 compared with 0.9 +/- 0.2mL per 24h in wild-type littermates; P=0.001). Accordingly, ambient urine osmolarity was markedly reduced (590 +/- 39 vs. 2216 +/- 132mosmolL(-1) in wild types; P<0.0001). During water restriction (24h), urinary osmolarity increased to 1633 +/- 153 and 3769 +/- 129mosmolL(-1) in ClC-K2-/- and wild-type mice (n=12; P<0.0001), accompanied by a loss of body weight of 12 +/- 0.4 and 8 +/- 0.2% respectively (P<0.0001). ClC-K2-/- mice showed an increased renal sodium excretion and compromised salt conservation during a salt-restricted diet. The salt-losing phenotype of ClC-K2-/- mice was associated with a reduced plasma volume, hypotension, a slightly reduced glomerular filtration rate, an increased renal prostaglandin E2 generation and a massively stimulated renin-angiotensin system. Clckb-/- mice showed a reduced sensitivity to furosemide and were completely resistant to thiazides. ConclusionLoss of ClC-K2 compromises TAL function and abolishes salt reabsorption in the distal convoluted tubule. Our data suggest that ClC-K2 is crucial for renal salt reabsorption and concentrating ability. ClC-K2-deficient mice in most aspects mimic patients with Bartter's syndrome type 3.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DISTAL CONVOLUTED TUBULE; CHLORIDE CHANNEL GENE; THICK ASCENDING LIMB; BARTTERS-SYNDROME; MACULA DENSA; MESSENGER-RNA; MUTANT MICE; HENLES LOOP; MOUSE MODEL; RAT-KIDNEY; Bartter's syndrome; chloride channels; Clckb; gene targeting |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Wolf Hayo Castrop |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Apr 2019 07:57 |
| Last Modified: | 24 Apr 2019 07:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4064 |
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