title: PKB/SGK-resistant GSK3 enhances phosphaturia and calciuria.
abstract: Insulin and IGF1-dependent signaling activates protein kinase B and serum and glucocorticoid inducible kinase (PKB/SGK), which together phosphorylate and inactivate glycogen synthase kinase GSK3. Because insulin and IGF1 increase renal tubular calcium and phosphorus reabsorption, we examined GSK3 regulation of phosphate transporter activity and determined whether PKB/SGK inactivates GSK3 to enhance renal phosphate and calcium transport. Overexpression of GSK3 and the phosphate transporter NaPi-IIa in Xenopus oocytes decreased electrogenic phosphate transport compared with NaPi-IIa-expressing oocytes. PKB/SGK serine phosphorylation sites in GSK3 were mutated to alanine to create gsk3(KI) mice resistant to PKB/SGK inactivation. Compared with wildtype animals, gsk3(KI) animals exhibited greater urinary phosphate and calcium clearances with higher excretion rates and lower plasma concentrations. Isolated brush border membranes from gsk3(KI) mice showed less sodium-dependent phosphate transport and Na-phosphate co-transporter expression. Parathyroid hormone, 1,25-OH vitamin D levels, and bone mineral density were decreased in gsk3(KI) mice, suggesting a global dysregulation of bone mineral metabolism. Taken together, PKB/SGK phosphorylation of GSK3 increases phosphate transporter activity and reduces renal calcium and phosphate loss.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Föller
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Kempe
authors.forename: Krishna M
authors.initials: KM
authors.lastname: Boini
authors.forename: Ganesh
authors.initials: G
authors.lastname: Pathare
authors.forename: Balasaheb
authors.initials: B
authors.lastname: Siraskar
authors.forename: Paola
authors.initials: P
authors.lastname: Capuano
authors.forename: Ioana
authors.initials: I
authors.lastname: Alesutan
authors.forename: Mentor
authors.initials: M
authors.lastname: Sopjani
authors.forename: Gerti
authors.initials: G
authors.lastname: Stange
authors.forename: Nilufar
authors.initials: N
authors.lastname: Mohebbi
authors.forename: Madhuri
authors.initials: M
authors.lastname: Bhandaru
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Ackermann
authors.forename: Martin S
authors.initials: MS
authors.lastname: Judenhofer
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Jürg
authors.initials: J
authors.lastname: Biber
authors.forename: Carsten A
authors.initials: CA
authors.lastname: Wagner
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D015519:Bone Density; D002117:Calcitriol / Q000097:blood; D002118:Calcium / Q000652:urine*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D007015:Hypophosphatemia, Familial / Q000209:etiology*; D017874:Immediate-Early Proteins / Q000502:physiology*; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D002117:Calcitriol; D002118:Calcium; D038362:Glycogen Synthase Kinase 3; D017874:Immediate-Early Proteins; D010281:Parathyroid Hormone; D010710:Phosphates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099184:Serum-Glucocorticoid Regulated Kinases