Review Article

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

Archie Brown1, Nur Farah Meor Azlan1, Zhijuan Wu1,2, Jinwei Zhang1,3
1 Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK
2 Newcastle University Business School, Newcastle University, Newcastle upon Tyne NE1 4SE, UK
3 Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen 361004, China
Correspondence to: Jinwei Zhang:,
DOI: 10.1038/s41401-020-0474-7
Received: 28 April 2020
Accepted: 6 July 2020
Advance online: 28 July 2020


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.
Keywords: WNK kinase; SPAK kinase; sodium chloride cotransporter NCC; chloride (Cl−) homeostasis; Gordon’s hypertension syndrome; therapeutic target.

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