Journal Mobile Options
Table of Contents
Vol. 28, No. 5, 2008
Issue release date: September 2008
Am J Nephrol 2008;28:707–714

Prolonged Endoplasmic Reticulum Stress Induces Apoptotic Cell Death in an Experimental Model of Chronic Cyclosporine Nephropathy

Han S.W. · Li C. · Ahn K.O. · Lim S.W. · Song H.G. · Jang Y.S. · Cho Y.M. · Jang Y.M. · Ghee J.Y. · Kim J.Y. · Kim S.H. · Kim J. · Kwon O.J. · Yang C.W.
aDivision of Nephrology, Department of Internal Medicine, bDepartment of Biochemistry, and cCell Death Research Center, Department of Anatomy, The Catholic University of Korea, Seoul, South Korea; dDepartment of Internal Medicine, The Affiliated Hospital, Yanbian University Medical College, Yanji, PR China

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background/Aims: 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. Conclusion: Prolonged CsA-induced ER stress causes apoptotic cell death by depleting molecular chaperones and activating the proapoptotic pathway.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Yang CW, Faulkner GR, Wahba IM, Christianson TA, Bagby GC, Jin DC, Abboud HE, Andoh TF, Bennett WM: Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice. Am J Transplant 2002;2:391–399.
  2. Shihab FS, Andoh TF, Tanner AM, Yi H, Bennett WM: Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis. Kidney Int 1999;56:2147–2159.
  3. Ito H, Kasagi N, Shomori K, Osaki M, Adachi H: Apoptosis in the human allografted kidney. Analysis by terminal deoxynucleotidyl transferase-mediated dutp-botin nick end labeling. Transplantation 1995;60:794–798.
  4. Thomas SE, Andoh TF, Pichler RH, Shankland SJ, Couser WG, Bennett WM, Johnson RJ: Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis. Kidney Int 1998;53:897–908.
  5. Elzinga LW, Rosen S, Bennett WM: Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol 1993;4:214–221.
  6. Rosen S, Greenfeld Z, Brezis M: Chronic cyclosporine-induced nephropathy in the rat. A medullary ray and inner stripe injury. Transplantation 1990;49:445–452.
  7. Mihatsch MJ, Antonovych T, Bohman SO, Habib R, Helmchen U, Noel LH, Olsen S, Sibley RK, Kemény E, Feutren G: Cyclosporin a nephropathy: standardization of the evaluation of kidney biopsies. Clin Nephrol 1994;41:23–32.
  8. Zhang K, Kaufman RJ: The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 2006;66(suppl 1):S102–S109.
  9. Okada K, Minamino T, Tsukamoto Y, Liao Y, Tsukamoto O, Takashima S, Hirata A, Fujita M, Nagamachi Y, Nakatani T, Yutani C, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M: Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 2004;110:705–712.
  10. Oyadomari S, Araki E, Mori M: Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells.Apoptosis 2002;7:335–345.
  11. Araki E, Oyadomari S, Mori M: Endoplasmic reticulum stress and diabetes mellitus. Intern Med 2003;42:7–14.
  12. Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H: Ask1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 2002;16:1345–1355.
  13. Yang CW, Ahn HJ, Kim WY, Li C, Jung JY, Yoon SA, Kim YS, Cha JH, Kim J, Bang BK: Synergistic effects of mycophenolate mofetil and losartan in a model of chronic cyclosporine nephropathy. Transplantation 2003;75:309–315.
  14. Li C, Yang CW, Kim WY, Jung JY, Cha JH, Kim YS, Kim J, Bennett WM, Bang BK: Reversibility of chronic cyclosporine nephropathy in rats after withdrawal of cyclosporine. Am J Physiol Renal Physiol 2003;284:F389–F398.
  15. Mori K: Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 2000;101:451–454.
  16. Boyce M, Yuan J: Cellular response to endoplasmic reticulum stress: a matter of life or death. Cell Death Differ 2006;13:363–373.
  17. Ferri KF, Kroemer G: Organelle-specific initiation of cell death pathways. Nat Cell Biol 2001;3:E255–E263.
  18. Rao RV, Ellerby HM, Bredesen DE: Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ 2004;11:372–380.
  19. Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC: Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003;22:8608–8618.
  20. Aridor M, Balch WE: Integration of endoplasmic reticulum signaling in health and disease. Nat Med 1999;5:745–751.
  21. Paschen W: Endoplasmic reticulum: A primary target in various acute disorders and degenerative diseases of the brain. Cell Calcium 2003;34:365–383.
  22. Bredesen DE, Rao RV, Mehlen P: Cell death in the nervous system. Nature 2006;443:796–802.
  23. Rutkowski DT, Kaufman RJ: A trip to the ER: coping with stress. Trends Cell Biol 2004;14:20–28.
  24. Gillardon F, Böttiger B, Schmitz B, Zimmermann M, Hossmann KA: Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Brain Res Mol Brain Res 1997;50:16–22.
  25. Harding HP, Ron D: Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002;51(suppl 3):S455–S461.
  26. Justo P, Lorz C, Sanz A, Egido J, Ortiz A: Intracellular mechanisms of cyclosporin A-induced tubular cell apoptosis.J Am Soc Nephrol 2003;14:3072–3080.
  27. Cummings BS, Gelasco AK, Kinsey GR, McHowat J, Schnellmann RG: Inactivation of endoplasmic reticulum bound Ca2+-independent phospholipase A2 in renal cells during oxidative stress. J Am Soc Nephrol 2004;15:1441–1451.
  28. Gotoh T, Mori M: Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol 2006;26:1439–1446.
  29. Kimura K, Jin H, Ogawa M, Aoe T: Dysfunction of the ER chaperone BiP accelerates the renal tubular injury. Biochem Biophys Res Commun 2008;366:1048–1053.
  30. Endo M, Mori M, Akira S, Gotoh T: C/ebp homologous protein (chop) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. J Immunol 2006;176:6245–6253.
  31. Bonilla M, Nastase KK, Cunningham KW: Essential role of calcineurin in response to endoplasmic reticulum stress. EMBO J 2002;21:2343–2353.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50