Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC
Por:
Argaiz, Eduardo R., Chavez-Canales, Maria, Ostrosky-Frid, Mauricio, Rodriguez-Gama, Alejandro, Vazquez, Norma, Gonzalez-Rodriguez, Xochiquetzal, Garcia-Valdes, Jesus, Hadchouel, Juliette, Ellison, David, Gamba, Gerardo
Publicada:
1 sep 2018
Resumen:
Familial hyperkalemic hypertension (FHHt) can be mainly attributed to
increased activity of the renal Na+:Cl- cotransporter (NCC), which is
caused by altered expression and regulation of the with-no-lysine (K) 1
(WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific
isoform that lacks the kinase domain (KS-WNK1), the expression of which
occurs primarily in the distal convoluted tubule. The role played by
KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase
(SPAK)/NCC pathway remains elusive. In the present study, we assessed
the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK
pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces
remarkable activation and phosphorylation of SPAK and NCC. The effect of
KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by
a specific WNK inhibitor, WNK463, indicating that the activation of
SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under
control conditions in oocytes, the activating serine 335 of the WNK4 T
loop is not phosphorylated. In contrast, this serine becomes
phosphorylated when the intracellular chloride concentration([Cl-](i))
is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated
activation of WNK4 is not due to a decrease of the [Cl-](i).
Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact
with each other and that WNK4 becomes autophosphorylated at serine 335
when it is associated with KS-WNK1. Together, these observations suggest
that WNK4 becomes active in the presence of KS-WNK1, despite a constant
[Cl-](i).
Filiaciones:
Argaiz, Eduardo R.:
Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico
Tecnol Monterrey, Escuela Med & Ciencias Salud, Monterrey, Nuevo Leon, Mexico
Chavez-Canales, Maria:
Univ Paris 06, Fac Med, INSERM, UMRS1155, Paris, France
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Translat Med Unit, Mexico City, DF, Mexico
Inst Nacl Cardiol Ignacio Chavez, Mexico City, DF, Mexico
Ostrosky-Frid, Mauricio:
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Med, PECEM, Mexico City, DF, Mexico
Rodriguez-Gama, Alejandro:
Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico
Vazquez, Norma:
Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico
Gonzalez-Rodriguez, Xochiquetzal:
Univ Nacl Autonoma Mexico, Dept Quim Analit, Fac Quim, Mexico City, DF, Mexico
Garcia-Valdes, Jesus:
Univ Nacl Autonoma Mexico, Dept Quim Analit, Fac Quim, Mexico City, DF, Mexico
Hadchouel, Juliette:
Univ Paris 06, Fac Med, INSERM, UMRS1155, Paris, France
Ellison, David:
Oregon Hlth & Sci Univ, Dept Med, Div Nephrol & Hypertens, Portland, OR 97201 USA
Vet Affairs Portland Hlth Care Syst, Portland, OR USA
Gamba, Gerardo:
Univ Nacl Autonoma Mexico, Mol Physiol Unit, Inst Invest Biomed, Mexico City, DF, Mexico
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Nephrol & Mineral Metab, Mexico City, DF, Mexico
Tecnol Monterrey, Escuela Med & Ciencias Salud, Monterrey, Nuevo Leon, Mexico
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