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J Physiol Volume 530, Number 3, 359-366, February 1, 2001
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Journal of Physiology (2001), 530.3, pp. 359-366
© Copyright 2001 The Physiological Society

Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics


Heddwen L. Brooks, Anne-Mette Sorensen, James Terris, Patrick J. Schultheis *, John N. Lorenz †, Gary E. Shull * and Mark A. Knepper


Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, * Department of Molecular Genetics, Biochemistry and Microbiology, and † Department of Molecular and Cellular Physiology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA

  1. The Na+-H+ exchanger NHE3 and the thiazide-sensitive Na+-Cl- cotransporter NCC are the major apical sodium transporters in the proximal convoluted tubule and the distal convoluted tubule of the kidney, respectively. We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice.

  2. We used a so-called 'targeted proteomics' approach, which profiles the entire renal tubule with regard to changes in Na+ transporter and aquaporin abundance in response to the gene deletions. Specific antibodies to the Na+ transporters and aquaporins expressed along the nephron were utilized to determine the relative abundance of each transporter. Semiquantitative immunoblotting was used which gives an estimate of the percentage change in abundance of each transporter in knockout compared with wild-type mice.

  3. In NHE3 knockout mice three changes were identified which could compensate for the loss of NHE3-mediated sodium absorption. (a) The proximal sodium-phosphate cotransporter NaPi-2 was markedly upregulated. (b) In the collecting duct, the 70 kDa form of the gamma-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance. This is thought to be an aldosterone-stimulated form of gamma-ENaC. (c) Glomerular filtration was significantly reduced.

  4. In the NCC knockout mice, amongst all the sodium transporters expressed along the renal tubule, only the 70 kDa form of the gamma-subunit of the epithelial sodium channel, ENaC, exhibited an increase in abundance.

  5. In conclusion, both mouse knockout models demonstrated successful compensation for loss of the deleted transporter. More extensive adaptation occurred in the case of the NHE3 knockout, presumably because NHE3 is responsible for much more sodium absorption in normal mice than in NCC knockout mice.




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