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The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

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Abstract

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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Acknowledgments

EJH is supported by the Dutch Kidney Foundation (KJPB 08.004) and the Netherlands Organisation for Scientific Research (Veni). NvdL is supported by the Netherlands Foundation for Cardiovascular Excellence. JL is supported by the Swiss National Science Foundation, the Swiss National Centre in Competence in Research Kidney CH, and the Zurich Centre for Integrative Human Physiology.

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  1. Department of Internal Medicine, Erasmus Medical Center, PO Box 2040, Room H-438, 3000 CA, Rotterdam, The Netherlands

    Arthur D. Moes, Nils van der Lubbe, Robert Zietse & Ewout J. Hoorn

  2. Institute of Anatomy, University of Zürich, Zürich, Switzerland

    Johannes Loffing

  3. Zurich Centre for Integrative Human Physiology, Zürich, Switzerland

    Johannes Loffing

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  1. Arthur D. Moes
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Correspondence to Ewout J. Hoorn.

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Moes, A.D., van der Lubbe, N., Zietse, R. et al. The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. Pflugers Arch - Eur J Physiol 466, 107–118 (2014). https://doi.org/10.1007/s00424-013-1407-9

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