title: Mutation of the Na(+)-K(+)-2Cl(-) cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia.
abstract: 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.
authors.affiliation: Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, Munich, Germany. kemter@lmb.uni-muenchen.de
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Lise
authors.initials: L
authors.lastname: Bankir
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewe
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Christina
authors.initials: C
authors.lastname: Landbrecht
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Boris
authors.initials: B
authors.lastname: Ivandic
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabé de Angelis
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Bernhard
authors.initials: B
authors.lastname: Aigner
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000235:genetics; D001835:Body Weight; D015519:Bone Density; D002118:Calcium / Q000097:blood; D003404:Creatinine / Q000097:blood; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005269:Femur / Q000000981:diagnostic imaging; D005838:Genotype; D006720:Homozygote; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007671:Kidney Concentrating Ability / Q000235:genetics*; D008274:Magnesium / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009088:Mucoproteins / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D011141:Polyuria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011859:Radiography; D012083:Renin / Q000378:metabolism; D012720:Severity of Illness Index; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics* / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014508:Urea / Q000097:blood*; D014527:Uric Acid / Q000097:blood; D058949:Uromodulin
chemical_list: D015415:Biomarkers; D008565:Membrane Proteins; D009088:Mucoproteins; C578714:SLC12A1 protein, human; C578715:Slc12a1 protein, mouse; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; C548612:UMOD protein, human; C548613:Umod protein, mouse; D058949:Uromodulin; D014527:Uric Acid; D014508:Urea; D003404:Creatinine; D000449:Aldehyde Reductase; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D012083:Renin; D008274:Magnesium; D002118:Calcium