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Endoplasmic reticulum stress with low-dose cyclosporine in frequently relapsing nephrotic syndrome

Authors
  • Hama, Taketsugu1
  • Nakanishi, Koichi1
  • Mukaiyama, Hironobu1
  • Shima, Yuko1
  • Togawa, Hiroko1
  • Sako, Mayumi2
  • Nozu, Kandai3
  • Iijima, Kazumoto3
  • Yoshikawa, Norishige1
  • 1 Wakayama Medical University, Department of Pediatrics, 811-1 Kimiidera, Wakayama, 641-8509, Japan , Wakayama (Japan)
  • 2 National Center for Child Health and Development, Division for Clinical Trials, Setagaya, Tokyo, Japan , Setagaya (Japan)
  • 3 Kobe University Graduate School of Medicine, Department of Pediatrics, Kobe, Hyogo, Japan , Kobe (Japan)
Type
Published Article
Journal
Pediatric Nephrology
Publisher
Springer-Verlag
Publication Date
Jan 15, 2013
Volume
28
Issue
6
Pages
903–909
Identifiers
DOI: 10.1007/s00467-012-2403-6
Source
Springer Nature
Keywords
License
Yellow

Abstract

BackgroundA 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).MethodsEndoplasmic 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.ResultsGRP78, 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.ConclusionsAn 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.

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