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Hypotension in NKCC1 null mice: role of the kidneys

¹Renal Division, Emory University School of Medicine, Atlanta, Georgia; ²Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; ³Renal Division, University of Texas Medical School, Houston, Texas; ⁴Departments of Molecular Genetics, Biochemistry and Microbiology and ⁵Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio; ⁶Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit Medical Campus of Case Western Reserve University School of Medicine, Detroit, Michigan; and ⁷Department of Physiology and Biophysics, College of Medicine, University of South Florida, Tampa, Florida

Submitted 1 August 2005 ; accepted in final form 1 September 2005

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) whether NKCC1 (–/–) mice have a defect in the regulation of NaCl and water balance, which might contribute to the observed hypotension and 2) whether 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 -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 aquaporin-1 (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.

Na⁺ transporters; chloride; water; renin; aldosterone

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