title: Functional consequences of integrin-linked kinase activation in podocyte damage.
abstract: BACKGROUND
  The delicate foot process architecture of glomerular podocytes critically depends on integrin mediated cell-glomerular basement membrane (GBM) interaction. Integrin signaling via the integrin-linked kinase (ILK) is activated in podocyte damage and associated with considerable podocyte phenotype alterations. ILK has been shown to regulate cell fate via nuclear interaction of beta-catenin with lymphoid enhancer factor (LEF-1) transcription factors. The aim of this study was to elucidate the molecular mechanisms of ILK dependant phenotype regulation in podocytes.
  
  
  METHODS
  ILK function was evaluated in conditionally immortalized murine glomerular epithelial cells using overexpression of ILK and a small molecule ILK inhibitor in puromycin/adriamycin-induced podocyte damage in vitro and in vivo.
  
  
  RESULTS
  Kinase active, but not mutant ILK induced translocation of beta-catenin to the cell nucleus, de novo expression of LEF-1, and nuclear colocalization of beta-catenin and LEF-1. The role of ILK signaling in podocyte damage was evaluated using puromycin, an agent known to cause selective proteinuria and to increase ILK activity. The small molecular ILK inhibitor MC-5 blocked puromycin-induced nuclear translocation of beta-catenin, podocyte detachment, cell proliferation, and repression of the slit membrane molecules P-cadherin and CD2ap. In vivo activation of the beta-catenin pathway could be shown by nuclear colocalization of beta-catenin with WT-1 in adriamycin nephropathy.
  
  
  CONCLUSIONS
  ILK regulates podocyte cell matrix interaction, proliferation, and slit membrane gene expression in podocyte damage. As this pathway is amendable to pharmacologic intervention, further detailed studies of in vivo ILK function in glomerular disease appear justified.
authors.affiliation: Medizinische Poliklinik, Universität München, Munich, Germany.
authors.forename: Vicente de Paulo Castro
authors.initials: Vde P
authors.lastname: Teixeira
authors.forename: Simone Monika
authors.initials: SM
authors.lastname: Blattner
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.forename: Clemens David
authors.initials: CD
authors.lastname: Cohen
authors.forename: Ilka
authors.initials: I
authors.lastname: Edenhofer
authors.forename: Novella
authors.initials: N
authors.lastname: Calvaresi
authors.forename: Monika
authors.initials: M
authors.lastname: Merkle
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D007678:Kidney Glomerulus / Q000473:pathology*; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin; D000099200:Scaffold Protein ILK
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C495267:CTNNB1 protein, mouse; C497574:Lef1 protein, mouse