Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal.
OBJECTIVE
To examine whether the reversibility of chronic cyclosporine A (CsA) nephrotoxicity is associated with apoptotic cell death and its regulatory factors.


METHODS
Chronic CsA nephrotoxicity was induced in Sprague-Dawley rats by administering CsA (15 mg/kg, sc) for 5 weeks, and then withdrawing it for 5 or 10 weeks. The effect of CsA withdrawal on apoptotic cell death was evaluated by an in situ TdT-mediated deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) assay and the expression of pro-apoptotic [transforming growth factor-beta 1 (TGF-beta 1) and Fas] and anti-apoptotic [epidermal growth factors (EGF) and Bcl-2] factors.


RESULTS
Discontinuation of CsA induced significant decreases in TUNEL-positive cells in a time-dependent manner and the reduction in TUNEL-positive cells was correlated with the tubulointerstitial fibrosis score (r=0.919, P<0.01). Upregulation of TGF-beta and Fas expression in CsA-treated rat kidneys was decreased significantly after withdrawal of CsA. In contrast, downregulated EGF and Bcl-2 expression returned to normal or supernormal levels.


CONCLUSIONS
CsA withdrawal is associated with a decrease in apoptotic cell death and with changes in the expression of pro-apoptotic and anti-apoptotic molecules involved in renal wound repair. This may constitute one of the mechanisms underlying the reversibility of chronic CsA nephrotoxicity.
Li
Can
C
Department of Internal Medicine, the Catholic University of Korea, Seoul 137-040, Korea.
Lim
Sun-woo
SW
Sun
Bo-kyung
BK
Choi
Bum-soon
BS
GLowacka
Sylvia
S
Cox
Akusib
A
Kelly
Darren
D
Kim
Yong-soo
YS
Kim
Jin
J
Bang
Byung-kee
BK
Yang
Chul-woo
CW
D000818:Animals; D017209:Apoptosis; D016572:Cyclosporine / Q000009:adverse effects*; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D053222:Fas Ligand Protein; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D016572:Cyclosporine