Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway

Pedro San-Cristobal, Diana Pacheco-Alvarez, Ciaran Richardson, Aaron M. Ring, Norma Vazquez, Fatema H. Rafiqi, Divya Chari, Kristopher T. Kahle, Qiang Leng, Norma A. Bobadilla, Steven C. Hebert, Dario R. Alessi, Richard P. Lifton, Gerardo Gamba

    Research output: Contribution to journalArticle

    175 Citations (Scopus)

    Abstract

    Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.

    Original languageEnglish
    Pages (from-to)4384-4389
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume106
    Issue number11
    Early online date24 Feb 2009
    DOIs
    Publication statusPublished - 17 Mar 2009

    Keywords

    • Angiotensin II receptor
    • Hypertension
    • Distal convoluted tubule
    • Salt reabsorption
    • Thiazide

    Cite this

    San-Cristobal, Pedro ; Pacheco-Alvarez, Diana ; Richardson, Ciaran ; Ring, Aaron M. ; Vazquez, Norma ; Rafiqi, Fatema H. ; Chari, Divya ; Kahle, Kristopher T. ; Leng, Qiang ; Bobadilla, Norma A. ; Hebert, Steven C. ; Alessi, Dario R. ; Lifton, Richard P. ; Gamba, Gerardo. / Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 11. pp. 4384-4389.
    @article{2e1c73d5b1df43bc8c7c44dd4fdcc70d,
    title = "Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway",
    abstract = "Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.",
    keywords = "Angiotensin II receptor, Hypertension, Distal convoluted tubule, Salt reabsorption, Thiazide",
    author = "Pedro San-Cristobal and Diana Pacheco-Alvarez and Ciaran Richardson and Ring, {Aaron M.} and Norma Vazquez and Rafiqi, {Fatema H.} and Divya Chari and Kahle, {Kristopher T.} and Qiang Leng and Bobadilla, {Norma A.} and Hebert, {Steven C.} and Alessi, {Dario R.} and Lifton, {Richard P.} and Gerardo Gamba",
    year = "2009",
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    doi = "10.1073/pnas.0813238106",
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    San-Cristobal, P, Pacheco-Alvarez, D, Richardson, C, Ring, AM, Vazquez, N, Rafiqi, FH, Chari, D, Kahle, KT, Leng, Q, Bobadilla, NA, Hebert, SC, Alessi, DR, Lifton, RP & Gamba, G 2009, 'Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 11, pp. 4384-4389. https://doi.org/10.1073/pnas.0813238106

    Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. / San-Cristobal, Pedro; Pacheco-Alvarez, Diana; Richardson, Ciaran; Ring, Aaron M.; Vazquez, Norma; Rafiqi, Fatema H.; Chari, Divya; Kahle, Kristopher T.; Leng, Qiang; Bobadilla, Norma A.; Hebert, Steven C.; Alessi, Dario R.; Lifton, Richard P.; Gamba, Gerardo.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 11, 17.03.2009, p. 4384-4389.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway

    AU - San-Cristobal, Pedro

    AU - Pacheco-Alvarez, Diana

    AU - Richardson, Ciaran

    AU - Ring, Aaron M.

    AU - Vazquez, Norma

    AU - Rafiqi, Fatema H.

    AU - Chari, Divya

    AU - Kahle, Kristopher T.

    AU - Leng, Qiang

    AU - Bobadilla, Norma A.

    AU - Hebert, Steven C.

    AU - Alessi, Dario R.

    AU - Lifton, Richard P.

    AU - Gamba, Gerardo

    PY - 2009/3/17

    Y1 - 2009/3/17

    N2 - Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.

    AB - Mutations in the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and high serum K+ levels (hyperkalemia). WNK4 has distinct functional states that regulate the balance between renal salt reabsorption and K+ secretion by modulating the activities of renal transporters and channels, including the Na-Cl cotransporter NCC and the K+ channel ROMK. WNK4's functions could enable differential responses to intravascular volume depletion (hypovolemia) and hyperkalemia. Because hypovolemia is uniquely associated with high angiotensin II (AngII) levels, AngII signaling might modulate WNK4 activity. We show that AngII signaling in Xenopus oocytes increases NCC activity by abrogating WNK4's inhibition of NCC but does not alter WNK4's inhibition of ROMK. This effect requires AngII, its receptor AT1R, and WNK4, and is prevented by the AT1R inhibitor losartan. NCC activity is also increased by WNK4 harboring mutations found in PHAII, and this activity cannot be further augmented by AngII signaling, consistent with PHAII mutations providing constitutive activation of the signaling pathway between AT1R and NCC. AngII's effect on NCC is also dependent on the kinase SPAK because dominant-negative SPAK or elimination of the SPAK binding motif in NCC prevent activation of NCC by AngII signaling. These effects extend to mammalian cells. AngII increases phosphorylation of specific sites on SPAK and NCC that are necessary for activation of each in mpkDCT cells. These findings place WNK4 in the signaling pathway between AngII and NCC, and provide a mechanism by which hypovolemia maximizes renal salt reabsoprtion without concomitantly increasing K+ secretion.

    KW - Angiotensin II receptor

    KW - Hypertension

    KW - Distal convoluted tubule

    KW - Salt reabsorption

    KW - Thiazide

    U2 - 10.1073/pnas.0813238106

    DO - 10.1073/pnas.0813238106

    M3 - Article

    VL - 106

    SP - 4384

    EP - 4389

    JO - Proceedings of the National Academy of Sciences

    JF - Proceedings of the National Academy of Sciences

    SN - 0027-8424

    IS - 11

    ER -