Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform.
With-no-lysine kinase-1 (WNK1) gene mutations cause familial hyperkalemic hypertension (FHHt), a Mendelian disorder of excessive renal Na+ and K+ retention. Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive Na-Cl cotransporter (NCC) activity. The predominant renal WNK1 isoform, KS-WNK1, expressed exclusively and at high levels in distal nephron, is a shorter kinase-defective product; the function of KS-WNK1 must therefore be kinase independent. Here, we report a novel role for KS-WNK1 as a dominant-negative regulator of L-WNK1. Na+ transport studies in Xenopus laevis oocytes demonstrate that KS-WNK1 downregulates NCC activity indirectly, by inhibiting L-WNK1. KS-WNK1 also associates with L-WNK1 in protein complexes in oocytes and attenuates L-WNK1 kinase activity in vitro. These observations suggest that KS-WNK1 plays an essential role in the renal molecular switch regulating Na+ and K+ balance; they provide insight into the kidney-specific phenotype of FHHt.
Subramanya
Arohan R
AR
Division of Nephrology and Hypertension, Oregon Health and Science University, PP262, 3314 SW US Veterans Hospital Road, Portland, OR 97239, USA.
Yang
Chao-Ling
CL
Zhu
Xiaoman
X
Ellison
David H
DH
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport; D017124:Conserved Sequence; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012964:Sodium / Q000378:metabolism; D000076204:WNK Lysine-Deficient Protein Kinase 1; D014982:Xenopus laevis
D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D015778:Minor Histocompatibility Antigens; D012964:Sodium; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C498744:Wnk1 protein, mouse; C410410:Wnk1 protein, rat