Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal

Can Li; Sun Woo Lim; Bo Kyung Sun; Bum Soon Choi; Sylvia Glowacka; Alison J. Cox; Darren J. Kelly; Yong Soo Kim; Jin Kim; Byung Kee Bang; Chul Woo Yang

Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal

Can Li
, Sun Woo Lim
, Bo Kyung Sun
, Bum Soon Choi
, Sylvia Glowacka
, Alison J. Cox
, Darren J. Kelly
, Yong Soo Kim
, Jin Kim
, Byung Kee Bang
, Chul Woo Yang

The Catholic University of Korea
Yanbian University
University of Melbourne

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

AIM: 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-beta1 (TGF-β1) 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-β1 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. CONCLUSION: 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.

Original language	English
Pages (from-to)	401-411
Number of pages	11
Journal	Acta Pharmacologica Sinica
Volume	25
Issue number	4
State	Published - Apr 2004

Bibliographical note

Funding Information:
The work performed in the authors' laboratory was helped financially by the Fonds Cancérologique de la Caisse Générale d'Epargne et de Retraite and by the Ministry of Agriculture. R. Kettmann and G. Marbaix are Maître de Recherche and L. Willems is Aspirant of the Fonds National de la Recherche Scientifique. A Van den Broeke is a Fellow of the Lady Tata Memorial Trust.

Keywords

Apoptosis
Bcl-2
Cyclosporine
Epidermal growth factor
Fas
Fibrosis
Transforming growth factor-beta

Cite this

@article{cb910828fb074639aec6bd99fe6bd015,

title = "Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal",

abstract = "AIM: 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-beta1 (TGF-β1) 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-β1 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. CONCLUSION: 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.",

keywords = "Apoptosis, Bcl-2, Cyclosporine, Epidermal growth factor, Fas, Fibrosis, Transforming growth factor-beta",

author = "Can Li and Lim, \{Sun Woo\} and Sun, \{Bo Kyung\} and Choi, \{Bum Soon\} and Sylvia Glowacka and Cox, \{Alison J.\} and Kelly, \{Darren J.\} and Kim, \{Yong Soo\} and Jin Kim and Bang, \{Byung Kee\} and Yang, \{Chul Woo\}",

note = "Funding Information: The work performed in the authors' laboratory was helped financially by the Fonds Canc{\'e}rologique de la Caisse G{\'e}n{\'e}rale d'Epargne et de Retraite and by the Ministry of Agriculture. R. Kettmann and G. Marbaix are Ma{\^i}tre de Recherche and L. Willems is Aspirant of the Fonds National de la Recherche Scientifique. A Van den Broeke is a Fellow of the Lady Tata Memorial Trust.",

year = "2004",

month = apr,

language = "English",

volume = "25",

pages = "401--411",

journal = "Acta Pharmacologica Sinica",

issn = "1671-4083",

publisher = "Springer Nature",

number = "4",

}

TY - JOUR

T1 - Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal

AU - Li, Can

AU - Lim, Sun Woo

AU - Sun, Bo Kyung

AU - Choi, Bum Soon

AU - Glowacka, Sylvia

AU - Cox, Alison J.

AU - Kelly, Darren J.

AU - Kim, Yong Soo

AU - Kim, Jin

AU - Bang, Byung Kee

AU - Yang, Chul Woo

N1 - Funding Information: The work performed in the authors' laboratory was helped financially by the Fonds Cancérologique de la Caisse Générale d'Epargne et de Retraite and by the Ministry of Agriculture. R. Kettmann and G. Marbaix are Maître de Recherche and L. Willems is Aspirant of the Fonds National de la Recherche Scientifique. A Van den Broeke is a Fellow of the Lady Tata Memorial Trust.

PY - 2004/4

Y1 - 2004/4

N2 - AIM: 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-beta1 (TGF-β1) 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-β1 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. CONCLUSION: 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.

AB - AIM: 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-beta1 (TGF-β1) 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-β1 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. CONCLUSION: 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.

KW - Apoptosis

KW - Bcl-2

KW - Cyclosporine

KW - Epidermal growth factor

KW - Fas

KW - Fibrosis

KW - Transforming growth factor-beta

UR - https://www.scopus.com/pages/publications/11144356531

M3 - Article

C2 - 15066204

AN - SCOPUS:11144356531

SN - 1671-4083

VL - 25

SP - 401

EP - 411

JO - Acta Pharmacologica Sinica

JF - Acta Pharmacologica Sinica

IS - 4

ER -

Expression of apoptosis-related factors in chronic cyclosporine nephrotoxicity after cyclosporine withdrawal

Abstract

Bibliographical note

Keywords

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