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WNK4 inhibits NCC protein expression through MAPK ERK1/2 signaling pathway
Author(s) -
Zhou Bo,
Zhang Yiqian,
Wang Dexuan,
Zhuang Jieqiu,
Zhang Xuemei,
Gu Dingying,
Cai Hui
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1002.21
Subject(s) - mapk/erk pathway , kinase , phosphorylation , protein kinase c , mitogen activated protein kinase 3 , medicine , endocrinology , pseudohypoaldosteronism , chemistry , signal transduction , microbiology and biotechnology , biology , hyperkalemia
WNK ((with no lysine (k)) kinase is a subfamily of serine/threonine kinases. Mutations in two members of this kinase family (WNK1 and WNK4) cause pseudohypoaldosteronism type II featuring hypertension, hyperkalemia and metabolic acidosis. WNK1 and WNK4 were shown to modulate NCC activity through SPAK and OSR1. Activation of PKC by a phorbol ester inhibits NCC function via activation of ERK1/2 kinase. To investigate whether WNK4 affects NCC via MAPK signaling pathway besides SPAK and OSR1, we first determine whether WNK4 phosphorylates ERK1/2 kinase. We found that WNK4 increases the phosphorylation of ERK1/2 in a dose‐dependent manner in mouse distal convoluted tubule (mDCT) cells, whereas WNK4 mutants with the PHA II mutations (E562K and R1185C) do not increase the ERK1/2 phosphorylation. We next showed that hypertonic stimulation significantly increased ERK1/2 phosphorylation in mDCT cells. The ERK1/2 activation by hypertonic stimulation was significantly attenuated by WNK4 siRNA knock‐down expression (23.19 ± 8.21 % in siWNK4 group vs 100 % in control group, p <0.01, n=3). We further showed that WNK4 knock‐down significantly increases total NCC expression (100 ± 0 % vs 120.7 ± 6.2 %, p <0.05, n=4) as well as NCC surface expression (100 ± 0 % vs 256.8 ± 50.3 %, p <0.05, n=4). We conclude that the inhibitory effect of WNK4 on NCC is mediated by MAPK ERK 1/2 signaling pathway. Note: BZ and YZ contributed equally to this work.