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The rapamycin derivative RAD inhibits mesangial cell migration through the CDK-inhibitor p27KIP1

Christoph Daniel1, Jeffrey Pippin, Stuart J Shankland

  • 1Medizinische Klinik IV, Universität Erlangen-Nürnberg, Erlangen, Germany.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|April 6, 2004
PubMed

Insights

The immunosuppressant RAD inhibits mesangial cell migration, impairing kidney repair. This effect is partly mediated by p27(KIP1), a cell cycle regulator, in both in vitro and in vivo models.

Area of Science:

  • Nephrology
  • Cell Biology
  • Immunology

Background:

  • Mesangial cell (MC) proliferation and migration are crucial for glomerular repair.
  • Similar pathways regulate cell cycle and migration, involving cell cycle proteins.
  • The immunosuppressant RAD inhibits MC proliferation via G1/S arrest and impairs glomerular healing.

Purpose of the Study:

  • To test if RAD alters MC migration in vitro and in vivo.
  • To determine if RAD's effect on MC migration is mediated by CDK-inhibitors p21(CIP1) and p27(KIP1).

Main Methods:

  • In vitro migration assay using a modified Boyden chamber with fibronectin-induced chemotaxis in wild-type (wt) MC.
  • Western blot analysis to assess p21(CIP1) and p27(KIP1) levels after RAD treatment.
  • In vivo study using the anti-Thy1 model with BrdU-labeling to track MC migration from the glomerular hilus.

Main Results:

  • RAD dose-dependently inhibited fibronectin-induced chemotaxis in wt MC.
  • RAD prevented the decrease in p27(KIP1) but not p21(CIP1) induced by mitogenic growth factors.
  • RAD significantly reduced MC migration in vivo and in vitro, with the effect dependent on p27(KIP1) but not p21(CIP1).

Conclusions:

  • The immunosuppressant RAD inhibits MC migration in vivo and in vitro, limiting glomerular repair.
  • RAD-induced inhibition of MC migration is partially mediated by the CDK-inhibitor p27(KIP1), not p21(CIP1).
  • Understanding RAD's impact on MC migration is crucial for managing kidney injury and repair.

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