title: Endoplasmic reticulum stress with low-dose cyclosporine in frequently relapsing nephrotic syndrome.
abstract: BACKGROUND
  A possible mechanism of cyclosporine (CsA) nephrotoxicity is tubular apoptosis. Endoplasmic reticulum (ER) stress has been shown to be an apoptosis activator. Glucose-regulated proteins 78 and 94 (GRP78, GRP94, respectively) are ER stress-induced chaperones. Eukaryotic translation initiation factor 2α (EIF2α) attenuates protein synthesis. If stress is prolonged, cells undergo apoptosis, inducing the production of GADD153, a transcription factor, which in turn downregulates anti-apoptotic protein B-cell lymphoma 2 (Bcl-2).
  
  
  METHODS
  Endoplasmic reticulum stress-related molecules were evaluated by real-time polymerase chain reaction (PCR) using renal biopsy tissues from 17 children with frequently relapsing nephrotic syndrome before and after 2 years of CsA therapy.
  
  
  RESULTS
  GRP78, GRP94, eIF2α, and Bcl-2 were significantly upregulated in renal biopsy tissues from children 2 years post-CsA treatment. However, there was almost no change in GADD153. Mean ratios of post- to pre-CsA expression of GRP78, GRP94, eIF2α and Bcl-2 were 2.53, 1.80, 2.38 and 1.92, respectively. Post-CsA administration, GRP78 and eIF2α were upregulated by up to sixfold, and GRP94 and Bcl-2 were upregulated by up to fourfold compared with the respective pre-CsA levels. There were significant correlations between GRP78, GRP94, eIF2α, and Bcl-2 levels. These findings suggest that CsA induced an unfolded protein response due to ER stress, but did not cause apoptosis.
  
  
  CONCLUSIONS
  An unfolded protein response due to ER stress induced by CsA may function in a defensive manner, with less apoptosis occurring under low-dose conditions. This finding is important for the rationale for CsA administration.
authors: Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors: Taketsugu
authors: T
authors: Hama
authors: Koichi
authors: K
authors: Nakanishi
authors: Hironobu
authors: H
authors: Mukaiyama
authors: Yuko
authors: Y
authors: Shima
authors: Hiroko
authors: H
authors: Togawa
authors: Mayumi
authors: M
authors: Sako
authors: Kandai
authors: K
authors: Nozu
authors: Kazumoto
authors: K
authors: Iijima
authors: Norishige
authors: N
authors: Yoshikawa
mesh_terms: D017209:Apoptosis; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000009:adverse effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000032:analysis; D005260:Female; D006360:Heat-Shock Proteins / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D009404:Nephrotic Syndrome / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; C053387:endoplasmin; D016572:Cyclosporine