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1 Renal Division, Emory University School of Medicine, Atlanta, GA, USA
2 Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
3 Renal Division, University of Texas Medical School, Houston, TX, USA
4 Departments of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
5 Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
6 Hypertension and Vascular Research Division, Detriot Medical Campus of Case Western Reserve University School of Medicine, Detroit, MI, USA
7 Department of Physiology and Biophysics, University of South Florida, College of Medicine, Tampa, FL, USA
* To whom correspondence should be addressed. E-mail: smwall{at}emory.edu.
NKCC1 null mice are hypotensive in part from the absence of NKCC1-mediated vasoconstriction.
Whether these mice have renal defects in NaCl and water handling which contribute to the hypotension is
unexplored. Therefore, we asked 1) if NKCC1 (-/-) mice have a defect in the regulation of NaCl and
water balance, which might contribute to the observed hypotension and 2) if the hypotension observed in
these mice is accompanied by endocrine abnormalities and/or downregulation of renal Na+ transporter
expression. Thus, we performed balance studies, semiquantitative immunoblotting and
immunohistochemistry of kidney tissue from NKCC1 (+/+) and NKCC1 (-/-) mice which consumed
either a high (2.8% NaCl) or a low NaCl (0.01% NaCl) diet for 7 days. Blood pressure was lower in
NKCC1 (-/-) than NKCC1 (+/+) mice following either high or low dietary NaCl intake. Relative to wild
type mice, NKCC1 null mice had a lower plasma ANP concentration, a higher plasma renin and a higher
serum K+ concentration with inappropriately low urinary K+ excretion, although serum aldosterone was
either the same or only slightly increased in the mutant mice. Expression of NHE3, the 
-1 subunit of
the Na,K-ATPase, NCC and NKCC2 were higher in NKCC1 null than in wild type mice, although
differences were generally greater during NaCl restriction. NKCC1 null mice had a reduced capacity to
excrete free water than wild type mice, which resulted in hypochloremia following the NaCl-deficient
diet. Hypochloremia did not occur from increased AQP1 or 2 protein expression or from redistribution of
AQP2 to the apical regions of principal cells. Instead, NKCC1 null mice had a blunted increase in urinary
osmolality following vasopressin administration, which should increase free water excretion and
attenuate the hypochloremia. In conclusion, aldosterone release is inappropriately low in NKCC1 null
mice. Moreover, the action of aldosterone and vasopressin is altered within kidneys of NKCC1 null mice,
which likely contributes to their hypotension. Increased Na+ transporter expression, increased plasma renin and reduced plasma ANP, as observed in NKCC1 null mice, should increase vascular volume and
blood pressure, thus minimizing hypotension.
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