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The cyclin-dependent kinase inhibitor p21 is required for TGF-beta1-induced podocyte apoptosis

Takehiko Wada1, Jeffrey W Pippin, Yoshio Terada

  • 1Division of Nephrology, University of Washington, Seattle, Washington 98195, USA.

Kidney International
|September 17, 2005
PubMed
Abstract

Insights

The cyclin-dependent kinase inhibitor p21 is essential for transforming growth factor-beta1 (TGF-beta1) and puromycin aminonucleoside-induced podocyte apoptosis. Bcl-2, an anti-apoptotic protein, plays a key role downstream of p21 in this process.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Reduced podocyte number is a key factor in glomerulosclerosis development.
  • Transforming growth factor-beta1 (TGF-beta1) induces podocyte apoptosis, but the underlying cell cycle events remain unclear.
  • The cyclin-dependent kinase (CDK) inhibitor p21 is upregulated in podocytes during diseases associated with increased TGF-beta.

Purpose of the Study:

  • To investigate the role of p21 in TGF-beta1-induced podocyte apoptosis.
  • To elucidate the cell cycle events involved in TGF-beta1-mediated podocyte apoptosis.
  • To determine the involvement of Bcl-2 family proteins in p21-dependent podocyte apoptosis.

Main Methods:

  • Utilized p21+/+ and p21-/- mouse podocytes (immortalized and primary).
  • Assessed apoptosis via Hoechst 33342 staining and caspase-3 activity after exposure to TGF-beta1 or puromycin aminonucleoside.
  • Measured p21 and Bcl-2 family protein levels using Western blot analysis; reconstituted p21 expression in p21-/- podocytes via adenovirus vector.

Main Results:

  • TGF-beta1 increased p21 levels and induced apoptosis in p21+/+ podocytes, but not in p21-/- podocytes.
  • Restoring p21 expression in p21-/- podocytes restored TGF-beta1-induced apoptosis.
  • TGF-beta1 increased anti-apoptotic Bcl-2 in p21-/- podocytes, an effect blocked by p21 re-expression; puromycin also induced apoptosis in a p21-dependent manner.

Conclusions:

  • Podocyte apoptosis induced by TGF-beta1 and puromycin aminonucleoside is dependent on p21.
  • Bcl-2 plays a critical role downstream of p21 in mediating TGF-beta1-induced podocyte apoptosis.
  • p21 is a critical factor in podocyte number reduction in diseases with elevated TGF-beta1.

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