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- Title
The cyclin-dependent kinase inhibitor p21 is required for TGF-β1–induced podocyte apoptosis.
- Authors
Wada, Takehiko; Pippin, Jeffrey W.; Terada, Yoshio; Shankland, Stuart J.
- Abstract
Background. Reduced podocyte number is a critical determinant in the development of glomerulosclerosis. Transforming growth factor-β1 (TGF-β1) induces podocyte apoptosis, but the cell cycle events are not known. The cyclin-dependent kinase (CDK) inhibitor p21 increases in podocytes in diseases where TGF-β increases. Accordingly, we studied the role of p21 in podocyte apoptosis. Methods. Immortalized and primary p21+/+ and p21−/− mouse podocytes were used. Apoptosis was measured by Hoechst 33342 staining and caspase-3 activity following the exposure to TGF-β1 or puromycin aminonucleoside. p21 and specific Bcl-2–related family proteins levels were measured by Western blot analysis. To prove a role for p21, we reconstituted p21 expression in p21−/− podocytes utilizing an adenovirus vector. Results. TGF-β1 increased the protein levels of p21 in p21+/+ podocytes, and this coincided with apoptosis. In contrast, TGF-β1 did not induce apoptosis in p21−/− podocytes. Restoring p21 expression increased apoptosis in p21−/− podocytes following exposure to TGF-β1. TGF-β1 increased the protein levels of an antiapoptotic Bcl-2 in p21−/− podocytes, but not in p21+/+ podocytes. Moreover, TGF-β1 did not increase Bcl-2 expression in p21−/− podocytes in which p21 expression was restored. Finally, puromycin aminonucleoside also induced apoptosis in p21+/+ podocytes, but not in p21−/− podocytes. Conclusion. Podocyte apoptosis induced by TGF-β1 and puromycin aminonucleoside requires p21, and Bcl-2 plays a crucial role downstream of p21 in mediating this effect. These results suggest that p21 may play a critical role in the decrease in podocyte number in disease status accompanied by increased TGF-β1.
- Subjects
GROWTH factors; APOPTOSIS; CELL cycle; CYCLIN-dependent kinases; CHEMICAL inhibitors; PUROMYCIN
- Publication
Kidney International, 2005, Vol 68, Issue 4, p1618
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1111/j.1523-1755.2005.00574.x