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)

    Research output: Contribution to journalArticle

    178 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

    Cite this

    Rafiqi, Fatema H. ; Zuber, Annie Mercier ; Glover, Mark ; Richardson, Ciaran ; Fleming, Stewart ; Jovanovic, Sofija ; Jovanovic, Aleksandar ; O'Shaughnessy, Kevin M. ; Alessi, Dario R. / Role of the WNK-activated SPAK kinase in regulating blood pressure. In: Embo Molecular Medicine. 2010 ; Vol. 2, No. 2. pp. 63-75.
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    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).",
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    author = "Rafiqi, {Fatema H.} and Zuber, {Annie Mercier} and Mark Glover and Ciaran Richardson and Stewart Fleming and Sofija Jovanovic and Aleksandar Jovanovic and O'Shaughnessy, {Kevin M.} and Alessi, {Dario R.}",
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    Rafiqi, FH, Zuber, AM, Glover, M, Richardson, C, Fleming, S, Jovanovic, S, Jovanovic, A, O'Shaughnessy, KM & Alessi, DR 2010, 'Role of the WNK-activated SPAK kinase in regulating blood pressure', Embo Molecular Medicine, vol. 2, no. 2, pp. 63-75. https://doi.org/10.1002/emmm.200900058

    Role of the WNK-activated SPAK kinase in regulating blood pressure. / Rafiqi, Fatema H.; Zuber, Annie Mercier; Glover, Mark; Richardson, Ciaran; Fleming, Stewart; Jovanovic, Sofija; Jovanovic, Aleksandar; O'Shaughnessy, Kevin M. (Lead / Corresponding author); Alessi, Dario R. (Lead / Corresponding author).

    In: Embo Molecular Medicine, Vol. 2, No. 2, 02.2010, p. 63-75.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Role of the WNK-activated SPAK kinase in regulating blood pressure

    AU - Rafiqi, Fatema H.

    AU - Zuber, Annie Mercier

    AU - Glover, Mark

    AU - Richardson, Ciaran

    AU - Fleming, Stewart

    AU - Jovanovic, Sofija

    AU - Jovanovic, Aleksandar

    AU - O'Shaughnessy, Kevin M.

    AU - Alessi, Dario R.

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    N2 - 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).

    AB - 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).

    KW - blood pressure

    KW - ion cotransporters

    KW - signal transduction

    KW - SPAK

    KW - WINK

    KW - NA+-CL-COTRANSPORTER

    KW - SODIUM-CHLORIDE COTRANSPORTER

    KW - HYPOKALEMIC ALKALOSIS

    KW - MOLECULAR PHYSIOLOGY

    KW - GITELMANS-SYNDROME

    KW - SIGNALING PATHWAY

    KW - BARTTERS-SYNDROME

    KW - MAMMALIAN-CELLS

    KW - PROTEIN-KINASES

    KW - MOUSE MODEL

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    DO - 10.1002/emmm.200900058

    M3 - Article

    VL - 2

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    EP - 75

    JO - Embo Molecular Medicine

    JF - Embo Molecular Medicine

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