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SGK1 attenuates WNK4‐mediated inhibition of thiazide‐sensitive NaCl cotransport
Author(s) -
Subramanya Arohan,
Cornwall Tonya,
Yang YongFeng,
Yang ChaoLing,
Ellison David,
Rozansky David
Publication year - 2006
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.20.5.lb29-c
Subject(s) - sgk1 , cotransporter , reabsorption , distal convoluted tubule , phosphorylation , aldosterone , symporter , chemistry , epithelial sodium channel , endocrinology , medicine , kinase , pseudohypoaldosteronism , microbiology and biotechnology , biology , biochemistry , kidney , transporter , gene , sodium , organic chemistry
In the late renal distal convoluted tubule (DCT2), WNK4 kinase inhibits electroneutral Na reabsorption by reducing surface expression of the thiazide‐sensitive NaCl cotransporter (NCC). WNK4 mutations cause Familial Hyperkalemic Hypertension (FHHt), a Mendelian disorder of impaired renal NaCl and K + excretion. Aldosterone enhances NCC activity in DCT2, at least in part by increasing its expression at the apical surface, but the underlying mechanism remains elusive. We reasoned that the aldosterone‐regulated kinase SGK1 might mediate this effect via WNK4, due to the presence of multiple canonical SGK1 phosphorylation motifs in the WNK4 sequence. 22 Na + transport studies in Xenopus oocytes demonstrated that WNK4 decreased NCC activity by 60% (p<0.01). SGK1, in either its constitutively active (S422D) or kinase dead (K127M) forms had no significant effect on NCC activity (p>0.05). In the presence of WNK4, S422D completely blocked WNK4‐mediated inhibition of NCC transport, restoring cotransporter activity to baseline levels; this effect was not seen with K127M. WNK4 and SGK1 associated in a protein complex in HEK 293 cells. In vitro kinase assays showed that SGK1 phosphorylates WNK4 at serine 1169, an FHHt‐associated residue that resides within a consensus SGK1 phosphorylation motif. In aggregate, these data suggest a mechanism where aldosterone enhances NCC surface expression by attenuating the actions of WNK4 on NCC via SGK1. Further characterization of this pathway may impact our understanding of human hypertension. Funding sources: NIDDK, NKF.