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 th e thick ascending limb and macula densa. This gene is one of several that w hen mutated causes Bartter's syndrome in humans, a syndrome characterized b y 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%). T hey subsequently failed to thrive. By day 7, they were small and markedly d ehydrated and exhibited renal insufficiency, high plasma potassium, metabol ic acidosis, hydronephrosis of varying severity, and high plasma renin conc entrations. None survived to weaning. Treatment of -/- pups with indomethac in from day 1 prevented growth retardation and 10% treated for 3 weeks surv ived, although as adults they exhibited severe polyuria (10 ml/day), extrem e hydronephrosis, low plasma potassium, high broad pH, hypercalciuria, and proteinuria. Wild-type mice treated with furosemide, an inhibitor of NaK2Cl cotransporters, have a phenotype similar to the indomethacin-rescued -/- a dults except that hydronephrosis was mild. The polyuria, hypercalciuria, an d proteinuria of the -/- adults and furosemide-treated wild-type mice were unresponsive to inhibitors of the renin angiotensin system, vasopressin, an d 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 aspe cts of genetic disturbances in water and electrolyte recovery by the kidney .