Prolonged endoplasmic reticulum stress induces apoptotic cell death in an experimental model of chronic cyclosporine nephropathy.
OBJECTIVE
Apoptosis contributes to cyclosporine (CsA)-induced renal cell death. This study tested the effects of CsA-induced endoplasmic reticulum (ER) stress on apoptotic cell death in an experimental model of chronic CsA nephropathy.


METHODS
CsA (15 mg/kg per day) was given to rats for 7 or 28 days. The ER stress response was evaluated with BiP expression, and the proapoptotic response was assessed with CHOP and caspase 12 expression. ER structure was evaluated by transmission electron microscopy, and apoptotic cell death was detected with TUNEL staining.


RESULTS
Short-term treatment of CsA for 7 days activated both the ER stress response (induction of BiP mRNA and protein) and the proapoptotic response (upregulation of caspase 12 and CHOP mRNAs and proteins). However, long-term treatment with CsA for 28 days decreased BiP and further increased CHOP. The imbalance between the two responses coincided with the timing of the appearance of apoptotic cell death and the disruption of the ER structure.


CONCLUSIONS
Prolonged CsA-induced ER stress causes apoptotic cell death by depleting molecular chaperones and activating the proapoptotic pathway.
Han
Sang Woo
SW
Department of Internal Medicine, Division of Nephrology, The Catholic University of Korea, Seoul, South Korea.
Li
Can
C
Ahn
Kyung Ohk
KO
Lim
Sun Woo
SW
Song
Hyun Guk
HG
Jang
Yoon Sung
YS
Cho
Yoon Mi
YM
Jang
Young Min
YM
Ghee
Jung Yeon
JY
Kim
Jin Young
JY
Kim
Su Hyun
SH
Kim
Jin
J
Kwon
Oh Joo
OJ
Yang
Chul Woo
CW
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D053454:Caspase 12 / Q000032:analysis; D016923:Cell Death; D016572:Cyclosporine; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051742:Transcription Factor CHOP / Q000032:analysis
D051742:Transcription Factor CHOP; D016572:Cyclosporine; D053454:Caspase 12