Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome.
ROMK is an apical K(+) channel expressed in the thick ascending limb of Henle (TALH) and throughout the distal nephron of the kidney. Null mutations in the ROMK gene cause type II Bartter's syndrome, in which abnormalities of electrolyte, acid-base, and fluid-volume homeostasis occur because of defective NaCl reabsorption in the TALH. To understand better the pathogenesis of type II Bartter's syndrome, we developed a mouse lacking ROMK and examined its phenotype. Young null mutants had hydronephrosis, were severely dehydrated, and approximately 95% died before 3 weeks of age. ROMK-deficient mice that survived beyond weaning grew to adulthood; however, they had metabolic acidosis, elevated blood concentrations of Na(+) and Cl(-), reduced blood pressure, polydipsia, polyuria, and poor urinary concentrating ability. Whole kidney glomerular filtration rate was sharply reduced, apparently as a result of hydronephrosis, and fractional excretion of electrolytes was elevated. Micropuncture analysis revealed that the single nephron glomerular filtration rate was relatively normal, absorption of NaCl in the TALH was reduced but not eliminated, and tubuloglomerular feedback was severely impaired. These data show that the loss of ROMK in the mouse causes perturbations of electrolyte, acid-base, and fluid-volume homeostasis, reduced absorption of NaCl in the TALH, and impaired tubuloglomerular feedback.
Department of Molecular Genetics, the University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
John N
JN
Lorenz
Nancy R
NR
Baird
Louise M
LM
Judd
William T
WT
Noonan
Anastasia
A
Andringa
Thomas
T
Doetschman
Patrice A
PA
Manning
Lynne H
LH
Liu
Marian L
ML
Miller
Gary E
GE
Shull
D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics*; D001483:Base Sequence; D001835:Body Weight; D017931:DNA Primers; D004195:Disease Models, Animal; D015723:Gene Library; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D008138:Loop of Henle / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012965:Sodium Chloride / Q000378:metabolism*; D013623:Tail
D017931:DNA Primers; D012965:Sodium Chloride