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Kemter, E.* ; Rathkolb, B.* ; Bankir, L.* ; Schrewe, A. ; Hans, W. ; Landbrecht, C.* ; Klaften, M. ; Ivandic, B.* ; Fuchs, H. ; Gailus-Durner, V. ; Hrabě de Angelis, M. ; Wolf, E.* ; Wanke, R.* ; Aigner, B.*

Mutation of the Na⁺-K⁺-2Cl‾ cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia.

Am. J. Physiol.-Renal Physiol. 298, F1405-F1415 (2010)
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The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords N-ethyl-N-nitrosourea; Renin; Solute carrier family 12 member 1
ISSN (print) / ISBN 0002-9513
e-ISSN 1522-1466
Journal American Journal of Physiology - Renal Physiology
Quellenangaben Volume: 298, Issue: 6, Pages: F1405-F1415 Article Number: , Supplement: ,
Publisher American Physiological Society
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)