Functional consequences of integrin-linked kinase activation in podocyte damage

Vicente De Paulo Castro Teixeira, Simone Monika Blattner, Min Li, Hans Joachim Anders, Clemens David Cohen, Ilka Edenhofer, Novella Calvaresi, Monika Merkle, Maria Pia Rastaldi, Matthias Kretzler

Research output: Contribution to journalArticlepeer-review

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 β-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 β-catenin to the cell nucleus, de novo expression of LEF-1, and nuclear colocalization of β-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 β-catenin, podocyte detachment, cell proliferation, and repression of the slit membrane molecules P-cadherin and CD2ap. In vivo activation of the β-catenin pathway could be shown by nuclear colocalization of β-catenin with WT-1 in adriamycin nephropathy. Conclusion. 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.

Original languageEnglish
Pages (from-to)514-523
Number of pages10
JournalKidney International
Volume67
Issue number2
DOIs
Publication statusPublished - Feb 2005

Keywords

  • Adriamycin
  • Glomerulus
  • ILK
  • P-cadherin
  • Puromycin
  • Wnt

ASJC Scopus subject areas

  • Nephrology

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