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

Lookup NU author(s): Dr Zhijuan Wu

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Abstract

© 2020, CPS and SIMM. 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.


Publication metadata

Author(s): Brown A, Meor Azlan NF, Wu Z, Zhang J

Publication type: Review

Publication status: Published

Journal: Acta Pharmacologica Sinica

Year: 2021

Volume: 42

Pages: 508-517

Print publication date: 01/04/2021

Online publication date: 28/07/2020

Acceptance date: 06/07/2020

ISSN (print): 1671-4083

ISSN (electronic): 1745-7254

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41401-020-0474-7

DOI: 10.1038/s41401-020-0474-7


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