title: Glycogen synthase kinase 3α regulates urine concentrating mechanism in mice.
abstract: In mammals, glycogen synthase kinase (GSK)3 comprises GSK3α and GSK3β isoforms. GSK3β has been shown to play a role in the ability of kidneys to concentrate urine by regulating vasopressin-mediated water permeability of collecting ducts, whereas the role of GSK3α has yet to be discerned. To investigate the role of GSK3α in urine concentration, we compared GSK3α knockout (GSK3αKO) mice with wild-type (WT) littermates. Under normal conditions, GSK3αKO mice had higher water intake and urine output. GSK3αKO mice also showed reduced urine osmolality and aquaporin-2 levels but higher urinary vasopressin. When water deprived, they failed to concentrate their urine to the same level as WT littermates. The addition of 1-desamino-8-d-arginine vasopressin to isolated inner medullary collecting ducts increased the cAMP response in WT mice, but this response was reduced in GSK3αKO mice, suggesting reduced responsiveness to vasopressin. Gene silencing of GSK3α in mpkCCD cells also reduced forskolin-induced aquaporin-2 expression. When treated with LiCl, an isoform nonselective inhibitor of GSK3 and known inducer of polyuria, WT mice developed significant polyuria within 6 days. However, in GSK3αKO mice, the polyuric response was markedly reduced. This study demonstrates, for the first time, that GSK3α could play a crucial role in renal urine concentration and suggest that GSK3α might be one of the initial targets of Li(+) in LiCl-induced nephrogenic diabetes insipidus.
authors.affiliation: Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark;
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Shixin
authors.initials: S
authors.lastname: Tao
authors.affiliation: Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark;
authors.forename: Line
authors.initials: L
authors.lastname: Nilsson
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: James R
authors.initials: JR
authors.lastname: Woodgett
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Kakade
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Alan S L
authors.initials: AS
authors.lastname: Yu
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Christiana
authors.initials: C
authors.lastname: Howard
authors.affiliation: The Kidney Institute, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas rrao@kumc.edu.
authors.forename: Reena
authors.initials: R
authors.lastname: Rao
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000201:enzymology*; D018021:Lithium Chloride; D018345:Mice, Knockout; D011141:Polyuria / Q000235:genetics; D014556:Urine / Q000502:physiology*
chemical_list: C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D018021:Lithium Chloride
keywords: glycogen synthase kinase 3α; glycogen synthase kinase 3β; lithium; urine concentration; vasopressin