title: Crosstalk between Smad and Mitogen-Activated Protein Kinases for the Regulation of Apoptosis in Cyclosporine A- Induced Renal Tubular Injury.
abstract: OBJECTIVE
  It remains elusive whether there is a crosstalk between Smad and mitogen-activated protein kinases (MAPKs) and whether it regulates cyclosporine A (CyA)-induced apoptosis in renal proximal tubular cells (RPTCs).
  
  
  METHODS
  The effect of CyA on nuclear translocation of Smad2/3 and MAPKs (measured by Western blotting or immunofluorescence) and apoptosis (determined by Hoechst 33258 staining) was examined in HK-2 cells.
  
  
  RESULTS
  CyA induced apoptosis at 24 h and nuclear translocation of phosphorylated (p)-Smad2/3 at 3 h, which was continued till 24 h. CyA enhanced the expression of p-ERK at 1 h, which was continued till 24 h, and of p-p38MAPK at 1-6 h, which returned to control level at 12 h. CyA did not affect JNK. An inhibitor of ERK, PD98059, prevented CyA-induced nuclear translocation of Smad2/3 and apoptosis. An inhibitor of p38MAPK, SB202190, deteriorated CyA-induced nuclear translocation of p-Smad2/3. Epidermal growth factor (EGF) activated ERK and p38MAPK but not JNK. EGF-induced activation of MAPKs ameliorated CyA-induced nuclear translocation of p-Smad2/3 and apoptosis. Inhibition of p38MAPK but not of ERK abolished the protective effect of EGF on CyA-induced nuclear translocation of p-Smad2/3 and apoptosis.
  
  
  CONCLUSIONS
  Crosstalk between R-Smad and p38MAPK/ERK, but not JNK differentially regulates apoptosis in CyA-induced RPTC injury.
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwayama
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nawa
authors.forename: Norishi
authors.initials: N
authors.lastname: Ueda