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WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension

Abstract

Hypertension is the most prevalent health condition worldwide, affecting ~1 billion people. Gordon’s syndrome is a form of secondary hypertension that can arise due to a number of possible mutations in key genes that encode proteins in a pathway containing the With No Lysine [K] (WNK) and its downstream target kinases, SPS/Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress responsive kinase 1 (OSR1). This pathway regulates the activity of the thiazide-sensitive sodium chloride cotransporter (NCC), which is responsible for NaCl reabsorption in the distal nephron. Therefore, mutations in genes encoding proteins that regulate the NCC proteins disrupt ion homeostasis and cause hypertension by increasing NaCl reabsorption. Thiazide diuretics are currently the main treatment option for Gordon’s syndrome. However, they have a number of side effects, and chronic usage can lead to compensatory adaptations in the nephron that counteract their action. Therefore, recent research has focused on developing novel inhibitory molecules that inhibit components of the WNK-SPAK/OSR1-NCC pathway, thereby reducing NaCl reabsorption and restoring normal blood pressure. In this review we provide an overview of the currently reported molecular inhibitors of the WNK-SPAK/OSR1-NCC pathway and discuss their potential as treatment options for Gordon’s syndrome.

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Fig. 1: Schematic representation of the WNK-SPAK-NCC pathway and WNK ubiquitination by the CUL3-KLHL3 E3 ubiquitin ligase complex.

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Acknowledgements

This study was in part supported by the University of Exeter Medical School start-up fund (JZ) and the National Natural Science Foundation of China 81970238 (JZ).

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Correspondence to Jinwei Zhang.

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Brown, A., Meor Azlan, N.F., Wu, Z. et al. WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension. Acta Pharmacol Sin 42, 508–517 (2021). https://doi.org/10.1038/s41401-020-0474-7

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Keywords

  • WNK kinase
  • SPAK kinase
  • sodium chloride cotransporter NCC
  • chloride (Cl) homeostasis
  • Gordon’s hypertension syndrome
  • therapeutic target.

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