title: The cyclin kinase inhibitor p57kip2 regulates TGF-beta-induced compensatory tubular hypertrophy: effect of the immunomodulator AS101.
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-beta 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 protein/DNA ratio were assessed for each experimental animal. The expression of TGF-beta, 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-beta 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 protein/DNA ratio, inhibited TGF-beta and p57(kip2) expression in the remaining kidneys, and decreased the level of p57(kip2) binding to cyclin E complexes.
  
  
  CONCLUSIONS
  These results demonstrate that TGF-beta-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.
authors.affiliation: Nephrology Division, Assaf Harofeh Medical Center, Zerifin, Israel. sinuanii@asaf.health.gov.il
authors.forename: Inna
authors.initials: I
authors.lastname: Sinuani
authors.forename: Joshua
authors.initials: J
authors.lastname: Weissgarten
authors.forename: Ilia
authors.initials: I
authors.lastname: Beberashvili
authors.forename: Micha J
authors.initials: MJ
authors.lastname: Rapoport
authors.forename: Judit
authors.initials: J
authors.lastname: Sandbank
authors.forename: Leonid
authors.initials: L
authors.lastname: Feldman
authors.forename: Michael
authors.initials: M
authors.lastname: Albeck
authors.forename: Zhan
authors.initials: Z
authors.lastname: Averbukh
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sredni