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Mechanisms of Disease: WNK-ing at the mechanism of salt-sensitive hypertension

Abstract

Potassium deficiency is associated with an increased prevalence of hypertension. Increasing potassium intake lowers blood pressure via an unknown mechanism. WNK (with no lysine) kinases are a novel family of large serine/threonine protein kinases. A large deletion from the first intron of the WNK1 gene results in increased levels of expression of WNK1 and causes Gordon's syndrome, of which hypertension and hyperkalemia are features. WNK1 activates the Na+/Cl cotransporter NCC and the epithelial Na+ channel ENaC, and inhibits the renal K+ channel ROMK. Enhanced Na+ reabsorption and inhibition of K+ secretion resulting from increased WNK1 expression probably contribute to hypertension and hyperkalemia in Gordon's syndrome. Here, we review the role of dietary K+ deficiency in the pathogenesis of salt-sensitive hypertension and summarize recent findings indicating that WNK1 might mediate renal Na+ retention and hypertension in K+ deficiency.

Key Points

  • Potassium deficiency causes obligatory sodium retention, thereby contributing to sustained hypertension by overriding mechanisms such as suppression of aldosterone and pressure-natriuresis

  • WNK1 (with no lysine) kinase 1, a novel serine/threonine kinase, enhances renal sodium reabsorption and inhibits potassium secretion

  • Potassium deficiency upregulates WNK1, thereby promoting conservation of potassium; however, sodium retention and hypertension also result

  • Potassium supplementation lowers blood pressure

  • Large deletions from the first intron of the WNK1 gene increase its expression, causing Gordon's syndrome (also known as pseudohypoaldosteronism type II), of which hypertension and hyperkalemia are features

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Figure 1: Relationship between daily sodium intake and prevalence of hypertension in different geographic areas.
Figure 2: Structure of long WNK1 and alternatively spliced kidney-specific WNK1.
Figure 3: The relationship between Na+ reabsorption and K+ secretion in the distal nephron.
Figure 4: A model of Na+ retention and hypertension in K+ deficiency.

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Acknowledgements

We thank Drs Peter Igarashi, Robert Reilly, Robert Toto, Orson Moe and Ronald Victor for suggestions and comments. Research in Chou-Long Huang's laboratory is supported by NIH grants (DK-59530 and DK-54368) and an American Heart Association grant (0440019N).

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Correspondence to Chou-Long Huang.

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Huang, CL., Kuo, E. Mechanisms of Disease: WNK-ing at the mechanism of salt-sensitive hypertension. Nat Rev Nephrol 3, 623–630 (2007). https://doi.org/10.1038/ncpneph0638

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  • DOI: https://doi.org/10.1038/ncpneph0638

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