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Kidney Int. 2016 Jan;89(1):127-34. doi: 10.1038/ki.2015.289. Epub 2016 Jan 4.

Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.

Author information

1
Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
2
Department of Nephrology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3
Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Universidad Nacional Autónoma de México, Mexico City, Mexico; Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
4
Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA; VA Portland Health Care System, Portland, OR, USA.
5
Division of Nephrology & Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA; VA Portland Health Care System, Portland, OR, USA. Electronic address: ellisond@ohsu.edu.

Abstract

Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low-potassium diet. Recent data suggest that plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the with-no-lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway. As previous studies used extreme dietary manipulations, we sought to determine whether the relationship between potassium and NaCl cotransporter (NCC) is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect NCC in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride concentration. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3, and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable it to mediate effects of potassium on NCC in vivo.

KEYWORDS:

cell signaling; distal convoluted tubule; mineral metabolism; potassium channels; thiazide-sensitive NaCl cotransporter

PMID:
26422504
PMCID:
PMC4814375
DOI:
10.1038/ki.2015.289
[Indexed for MEDLINE]
Free PMC Article

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