Role of the WNK-activated SPAK kinase in regulating blood pressure

Fatema H. Rafiqi, Annie Mercier Zuber, Mark Glover, Ciaran Richardson, Stewart Fleming, Sofija Jovanovic, Aleksandar Jovanovic, Kevin M. O'Shaughnessy (Lead / Corresponding author), Dario R. Alessi (Lead / Corresponding author)

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    191 Citations (Scopus)

    Abstract

    Mutations within the with-no-K(Lys) (WNK) kinases cause Gordon's syndrome characterized by hypertension and hyperkalaemia. WNK kinases phosphorylate and activate the STE20/SPS1-related proline/alanine-rich kinase (SPAK) protein kinase, which phosphorylates and stimulates the key Na+:Cl- cotransporter (NCC) and Na+:K+:2Cl(-) cotransporters (NKCC2) cotransporters that control salt reabsorption in the kidney. To define the importance of this pathway in regulating blood pressure, we generated knock-in mice in which SPAK cannot be activated by WINKS. The SPAK knock-in animals are viable, but display significantly reduced blood pressure that was salt-dependent. These animals also have markedly reduced phosphorylation of NCC and NKCC2 cotransporters at the residues phosphorylated by SPAK. This was also accompanied by a reduction in the expression of NCC and NKCC2 protein without changes in messenger RNA (mRNA) levels. On a normal Na+-diet, the SPAK knock-in mice were normokalaemic, but developed mild hypokalaemia when the renin-angiotensin system was activated by a low Na+-diet. These observations establish that SPAK plays an important role in controlling blood pressure in mammals. Our results imply that SPAK inhibitors would be effective at reducing blood pressure by lowering phosphorylation as well as expression of NCC and NKCC2. See accompanying Closeup by Maria Castaneda-Bueno and Gerald Gamba (DOI 10.1002/emmm.200900059).

    Original languageEnglish
    Pages (from-to)63-75
    Number of pages13
    JournalEmbo Molecular Medicine
    Volume2
    Issue number2
    DOIs
    Publication statusPublished - Feb 2010

    Keywords

    • blood pressure
    • ion cotransporters
    • signal transduction
    • SPAK
    • WINK
    • NA+-CL-COTRANSPORTER
    • SODIUM-CHLORIDE COTRANSPORTER
    • HYPOKALEMIC ALKALOSIS
    • MOLECULAR PHYSIOLOGY
    • GITELMANS-SYNDROME
    • SIGNALING PATHWAY
    • BARTTERS-SYNDROME
    • MAMMALIAN-CELLS
    • PROTEIN-KINASES
    • MOUSE MODEL

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