title: PKB/SGK-resistant GSK-3 signaling following unilateral ureteral obstruction.
abstract: OBJECTIVE
  Renal tissue fibrosis contributes to the development of end-stage renal disease. Causes for renal tissue fibrosis include obstructive nephropathy. The development of renal fibrosis following unilateral ureteral obstruction (UUO) is blunted in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1. Similar to Akt isoforms, SGK1 phosphorylates and thus inactivates glycogen synthase kinase GSK-3. The present study explored whether PKB/SGK-dependent phoshorylation of GSK-3α/β impacts on pro-fibrotic signaling following UUO.
  
  
  METHODS
  UUO was induced in mice carrying a PKB/SGK-resistant GSK-3α/β (gsk-3(KI)) and corresponding wild-type mice (gsk-3(WT)). Three days after the obstructive injury, expression of fibrosis markers in kidney tissues was analyzed by quantitative RT-PCR and western blotting.
  
  
  RESULTS
  GSK-3α and GSK-3β phosphorylation was absent in both, the non-obstructed and the obstructed kidney tissues from gsk-3(KI) mice but was increased by UUO in kidney tissues from gsk-3(WT) mice. Expression of α-smooth muscle actin, type I collagen and type III collagen in the non-obstructed kidney tissues was not significantly different between gsk-3(KI) mice and gsk-3(WT) mice but was significantly less increased in the obstructed kidney tissues from gsk-3(KI) mice than from gsk-3(WT) mice. After UUO treatment, renal β-catenin protein abundance and renal expression of the β-catenin sensitive genes: c-Myc, Dkk1, Twist and Lef1 were again significantly less increased in kidney tissues from gsk-3(KI) mice than from gsk-3(WT) mice.
  
  
  CONCLUSIONS
  PKB/SGK-dependent phosphorylation of glycogen synthase kinase GSK-3 contributes to the pro-fibrotic signaling leading to renal tissue fibrosis in obstructive nephropathy.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Voelkl
authors.forename: Sobuj
authors.initials: S
authors.lastname: Mia
authors.forename: Adrian
authors.initials: A
authors.lastname: Meissner
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Martina
authors.initials: M
authors.lastname: Feger
authors.forename: Bernat
authors.initials: B
authors.lastname: Elvira
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Ioana
authors.initials: I
authors.lastname: Alesutan
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D003094:Collagen / Q000096:biosynthesis; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014517:Ureteral Obstruction / Q000235:genetics / Q000503:physiopathology*; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000502:physiology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D003094:Collagen; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D051176:beta Catenin; D000099184:Serum-Glucocorticoid Regulated Kinases; C000605507:Gsk3b protein, mouse; C448021:glycogen synthase kinase 3 alpha