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*Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; National Heart Lung and Blood Institute, National Institute of Health, Bethesda, Maryland; Department of Physiology, University of Maryland, Baltimore, Maryland; Department of Pediatrics and |Department of Nephrology, Hypertension and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Correspondence to: Dr. Oliver Smithies, Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525. Phone: 919-966-6912; Fax: 919-966-8800; E-mail: ntakaha{at}med.unc.edu
ABSTRACT. Mice homozygous for a loss of function mutation of the kidney-specific NaK2Cl cotransporter, BSC1/NKCC2, do not survive. Here the effects of loss of one copy of the gene are studied. NKCC2 mRNA of NKCC2 +/- kidney was 55 ± 6% of +/+, yet no differences were found between NKCC2 +/+ and +/- mice in BP, blood gas, electrolytes, creatinine, plasma renin concentration, urine volume and osmolality, ability to concentrate and dilute urine, and response to furosemide. When mice were challenged with 180 mM NH4Cl, plasma ammonia and urinary ammonia excretion were increased twofold and fivefold, respectively, but there was still no difference between the two genotypes. NKCC2 +/- mice had a near-normal level of NKCC2 protein and no clear change in the distribution of NKCC2 in the thick ascending limb (TAL) cells. In vitro microperfusion of isolated TAL showed no significant difference between the two genotypes in the basal and vasopressin-stimulated capacity to reabsorb NaCl. There was no difference in the mRNA expressions of thiazide-sensitive NaCl cotransporter, epithelial Na channel (ENaC), aquaporin-2, ROMK, and NaKATPase. Halving the mRNA expression of NKCC2 does not affect BP or fluid balance because of compensatory factors that restore the protein level to near normal. One possible factor is a regulated increase in the movement of cytoplasmic protein to the luminal membrane leading to a restoration of functional transporter to an essentially wild type level.
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