Uncompensated polyuria in a mouse model of Bartter's syndrome.
We have used homologous recombination to disrupt the mouse gene coding for the NaK2Cl cotransporter (NKCC2) expressed in kidney epithelial cells of the thick ascending limb and macula densa. This gene is one of several that when mutated causes Bartter's syndrome in humans, a syndrome characterized by severe polyuria and electrolyte imbalance. Homozygous NKCC2-/- pups were born in expected numbers and appeared normal. However, by day 1 they showed signs of extracellular volume depletion (hematocrit 51%; wild type 37%). They subsequently failed to thrive. By day 7, they were small and markedly dehydrated and exhibited renal insufficiency, high plasma potassium, metabolic acidosis, hydronephrosis of varying severity, and high plasma renin concentrations. None survived to weaning. Treatment of -/- pups with indomethacin from day 1 prevented growth retardation and 10% treated for 3 weeks survived, although as adults they exhibited severe polyuria (10 ml/day), extreme hydronephrosis, low plasma potassium, high blood pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin-rescued -/- adults except that hydronephrosis was mild. The polyuria, hypercalciuria, and proteinuria of the -/- adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, and further indomethacin. Thus absence of NKCC2 in the mouse causes polyuria that is not compensated elsewhere in the nephron. The NKCC2 mutant animals should be valuable for uncovering new pathophysiologic and therapeutic aspects of genetic disturbances in water and electrolyte recovery by the kidney.
Takahashi
N
N
Department of Pathology and Laboratory Medicine and Division of Nephrology, University of North Carolina, Chapel Hill, NC 27599, USA. ntakaha@med.unc.edu
Chernavvsky
D R
DR
Gomez
R A
RA
Igarashi
P
P
Gitelman
H J
HJ
Smithies
O
O
D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D004573:Electrolytes / Q000097:blood; D006869:Hydronephrosis / Q000235:genetics / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007438:Introns; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D011141:Polyuria / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011188:Potassium / Q000097:blood; D011401:Promoter Regions, Genetic; D011507:Proteinuria; D012083:Renin / Q000097:blood; D028021:Sodium-Potassium-Chloride Symporters
D002352:Carrier Proteins; D004573:Electrolytes; D008565:Membrane Proteins; D028021:Sodium-Potassium-Chloride Symporters; D012083:Renin; D011188:Potassium; D002118:Calcium; D007213:Indomethacin