Apoptosis by cyclosporine in mesangial cells.
BACKGROUND
The immunosuppressive agent cyclosporine (CsA) is widely used to treat allograft rejection and various autoimmune disorders. A major limiting factor in the use of CsA is chronic nephrotoxicity. The pathogenesis of CsA-induced nephrotoxicity is not fully understood. Several recent studies have suggested that CsA treatment directly induces apoptosis in several cell types. The present study was undertaken to investigate the effects of CsA on apoptosis of cultured rat mesangial cells (RMCs).


METHODS
RMCs were treated with CsA at concentrations of 0.1 to 40 mumol/L. Cell viability was determined by MTT assay. Apoptotic protein expression was determined by Western blot analysis.


RESULTS
Cell viability was decreased with increasing concentrations of CsA in dose-dependent manner. CsA produced dose-dependent induction of p53, caspase-6, and Bax protein expression. CsA treatment caused proteolytic cleavage of caspase-3 and induced the degradation of 116-kDa PARP into 89-kDa fragment. RMCs with CsA reduced Bcl-2 and cIAP expression.


CONCLUSIONS
In this study, CsA induced apoptosis by up-regulating proapoptotic factors, caspase-3 and -6, p53, Bax, cleaving PARP, and down-regulating antiapoptotic factor, Bcl-2, and cIAP. These results suggested that the increased cell apoptosis exerted by CsA may be one of the mechanisms promoting CsA-induced nephrotoxicity.
Han
S Y
SY
Dongsan Kidney Institute and Chronic Disease Research Center, Keimyung University School of Medicine, 194 Dong San Dong, Daegu 700-712, Korea.
Chang
E J
EJ
Choi
H J
HJ
Kwak
C S
CS
Park
S B
SB
Kim
H C
HC
Mun
K C
KC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats
D016572:Cyclosporine