title: Cell-specific regulation of L-WNK1 by dietary K.
abstract: Flow-induced K(+) secretion in the aldosterone-sensitive distal nephron is mediated by high-conductance Ca(2+)-activated K(+) (BK) channels. Familial hyperkalemic hypertension (pseudohypoaldosteronism type II) is an inherited form of hypertension with decreased K(+) secretion and increased Na(+) reabsorption. This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs. We examined whether the full-length (or "long") form of WNK1 (L-WNK1) affected the expression of BK α-subunits in HEK cells. Overexpression of L-WNK1 promoted a significant increase in BK α-subunit whole cell abundance and functional channel expression. BK α-subunit abundance also increased with coexpression of a kinase dead L-WNK1 mutant (K233M) and with kidney-specific WNK1 (KS-WNK1), suggesting that the catalytic activity of L-WNK1 was not required to increase BK expression. We examined whether dietary K(+) intake affected L-WNK1 expression in the aldosterone-sensitive distal nephron. We found a paucity of L-WNK1 labeling in cortical collecting ducts (CCDs) from rabbits on a low-K(+) diet but observed robust staining for L-WNK1 primarily in intercalated cells when rabbits were fed a high-K(+) diet. Our results and previous findings suggest that L-WNK1 exerts different effects on renal K(+) secretory channels, inhibiting renal outer medullary K(+) channels and activating BK channels. A high-K(+) diet induced an increase in L-WNK1 expression selectively in intercalated cells and may contribute to enhanced BK channel expression and K(+) secretion in CCDs.
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Tennille N
authors.initials: TN
authors.lastname: Webb
authors.affiliation: Department of Pediatrics, The Icahn School of Medicine at Mount Sinai, New York, New York; and.
authors.forename: Rolando
authors.initials: R
authors.lastname: Carrisoza-Gaytan
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montalbetti
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Anna
authors.initials: A
authors.lastname: Rued
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Ankita
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Socovich
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
authors.forename: Arohan R
authors.initials: AR
authors.lastname: Subramanya
authors.affiliation: Department of Pediatrics, The Icahn School of Medicine at Mount Sinai, New York, New York; and.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Satlin
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; kleyman@pitt.edu.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kleyman
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Marcelo D
authors.initials: MD
authors.lastname: Carattino
mesh_terms: D000818:Animals; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000201:enzymology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D017419:Potassium, Dietary / Q000008:administration & dosage / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D065667:Renal Elimination; D014162:Transfection; D015854:Up-Regulation; D000076204:WNK Lysine-Deficient Protein Kinase 1
chemical_list: C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D015778:Minor Histocompatibility Antigens; D017419:Potassium, Dietary; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498744:Wnk1 protein, mouse
keywords: high-conductance calcium-activated potassium channels; kidney-specific with-no-lysine kinase 1; long with-no-lysine kinase 1; potassium adaptation; pseudohypoaldosteronism; with-no-lysine kinase 1