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The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway

Abstract

Renal salt handling has a profound effect on body fluid and blood pressure (BP) maintenance as exemplified by the use of diuretic medications to treat states of volume expansion or hypertension. It has recently been proposed that a low potassium (K+) intake turns on a “renal K+ switch” which increases sodium (Na+) and chloride (Cl) reabsorption, causing salt-retention, and in susceptible individuals, this causes hypertension. A signaling network, involving with-no-lysine (WNK) kinases, underpins the switch activity to coordinate aldosterone’s two essential actions (K+ secretion and Na+ retention). A dysfunctional WNK kinase network drives excessive and inappropriate Na+, Cl and urinary K+ retention in familial hyperkalemic hypertension (FHHt, also known as Gordon’s syndrome). Mutations in genes encoding WNK1 and WNK4 or components of an ubiquitin ligase complex, cullin3, and kelch-like family member 3 (KLHL3), cause FHHt by upregulating the thiazide-sensitive sodium chloride cotransporter (NCC). Inhibition of NCC with thiazide diuretics corrects hypertension and hyperkalaemia in FHHt. These observations highlight the critical role of the NCC in the regulation of Na+ and K+ balance and of BP. Here we discuss the physiology of Na+ and K+ handling in the distal renal tubule with respect to BP regulation, with a focus on recent discoveries in the WNK- Ste20-related proline-alanine-rich kinase (SPAK)-NCC pathway.

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Acknowledgements

We thank the Leducq Foundation for financial support of potassium in hypertension research.

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MS is currently Editor-in-Chief of the Journal of Human Hypertension, necessitating handling of the manuscript by one of the other co-editors. The remaining authors declare no conflict of interest.

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Wu, A., Wolley, M. & Stowasser, M. The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway. J Hum Hypertens 33, 508–523 (2019). https://doi.org/10.1038/s41371-019-0170-6

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