Loss of α(E)-catenin potentiates cisplatin-induced nephrotoxicity via increasing apoptosis in renal tubular epithelial cells

Toxicol Sci. 2014 Sep;141(1):254-62. doi: 10.1093/toxsci/kfu130. Epub 2014 Jun 27.


Cisplatin is one of the most potent and widely used antitumor drugs. However, the use of cisplatin is limited by its side effect, nephrotoxicity. Evidence has shown an increased incidence and severity of acute kidney injury (AKI) in the elderly. Previous studies from our laboratory demonstrate a decrease in α(E)-catenin expression in aged kidney. In this study, we investigated whether the loss of α(E)-catenin may increase cisplatin nephrotoxicity. To study the effects of reduced α(E)-catenin, a cell line with stable knockdown of α(E)-catenin (C2 cells) was used; NT3 is nontargeted control. C2 cells exhibited a significant loss of viability as determined by MTT assay compared with NT3 cells after cisplatin challenge, but showed no difference in lactate dehydrogenase (LDH) leakage. Increased caspase 3/7 activation and PARP cleavage was observed in C2 cells after cisplatin treatment. Z-VAD, a pan-caspase inhibitor, abolished the difference in susceptibility between NT3 and C2 cells. Interestingly, the expression of α(E)-catenin was further decreased after cisplatin treatment. Furthermore, in vivo data demonstrated a significant increase in serum creatinine at 72 h after a single dose of cisplatin in 24-month-old rats, but not in 4-month-old rats. Increased expression of KIM-1 and in situ apoptosis were also detected in aged kidney after cisplatin challenge. Taken together, these data suggest that loss of α(E)-catenin increases apoptosis of tubular epithelial cells which may contribute to the increased nephrotoxicity induced by cisplatin in aged kidney.

Keywords: AKI; aging; apoptosis; cisplatin; α-catenin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Line
  • Cell Survival / drug effects
  • Cisplatin / toxicity*
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Gene Knockdown Techniques
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / genetics
  • Kidney Diseases / pathology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Kidney Tubules, Proximal / pathology
  • Male
  • Rats, Inbred F344
  • Real-Time Polymerase Chain Reaction
  • alpha Catenin / genetics
  • alpha Catenin / physiology*


  • Antineoplastic Agents
  • alpha Catenin
  • Cisplatin