The cyclin kinase inhibitor p57 kip2 regulates TGF-β-induced compensatory tubular hypertrophy: Effect of the immunomodulator AS101

Inna Sinuani, Joshua Weissgarten, Ilia Beberashvili, Micha J. Rapoport, Judit Sandbank, Leonid Feldman, Michael Albeck, Zhan Averbukh, Benjamin Sredni

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-β secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon.Methods. A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and proteinDNA ratio were assessed for each experimental animal. The expression of TGF-β, PCNA, CDK 2, pRb, ppRb, p21 Waf1, p27 kip1 and p57 kip2 proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed.Results. Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-β expression were positively correlated with the amounts of p57 kip2, but not with p21 Waf1 and p27 kip1 expression in the remaining kidneys. Moreover, there was a marked abundance of p57 kip2 but not p21 Waf1 and p27 kip1 binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and proteinDNA ratio, inhibited TGF-β and p57 kip2 expression in the remaining kidneys, and decreased the level of p57 kip2 binding to cyclin E complexes.Conclusion. These results demonstrate that TGF-β-induced compensatory tubular cell hypertrophy is regulated in vivo by p57 kip2 but not by the p21 Waf1 and p27 kip1 cyclin kinase inhibitor proteins.

Original languageEnglish
Pages (from-to)2328-2338
Number of pages11
JournalNephrology Dialysis Transplantation
Volume24
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

Keywords

  • Cell cycle
  • Compensatory renal growth
  • Cyclin kinase inhibitor proteins
  • Hypertrophy
  • Transforming growth factor-β

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