title: Prolonged endoplasmic reticulum stress induces apoptotic cell death in an experimental model of chronic cyclosporine nephropathy.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Nephrology, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sang Woo
authors.initials: SW
authors.lastname: Han
authors.forename: Can
authors.initials: C
authors.lastname: Li
authors.forename: Kyung Ohk
authors.initials: KO
authors.lastname: Ahn
authors.forename: Sun Woo
authors.initials: SW
authors.lastname: Lim
authors.forename: Hyun Guk
authors.initials: HG
authors.lastname: Song
authors.forename: Yoon Sung
authors.initials: YS
authors.lastname: Jang
authors.forename: Yoon Mi
authors.initials: YM
authors.lastname: Cho
authors.forename: Young Min
authors.initials: YM
authors.lastname: Jang
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Ghee
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Su Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
authors.forename: Oh Joo
authors.initials: OJ
authors.lastname: Kwon
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: 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
chemical_list: D051742:Transcription Factor CHOP; D016572:Cyclosporine; D053454:Caspase 12