Cyclosporine (CsA) nephrotoxicity shows characteristic tubular vacuolization (TV) which is endoplasmic reticulum (ER) in origin. However, the cellular events of CsA-induced TV and CsA-induced ER remained unclear. The aim of the present study was to study the nature of TV and the correlation to ER stress. Using proximal tubule NRK-52E cells in vitro and an in vivo model of acute CsA nephrotoxicity, we confirmed that CsA-induced TV was ER in origin and potentially reversible. Our results showed that CsA-induced ER stress and involved ER integrated stress response-related proteins (Bip/Grp78, ATF6, IRE1 and CHOP) but not cytoplasmic ER stress-related chaperones (HSP70, HSP40, HSP27, HSP90 and HSP60). Importantly, Bip/Grp78 was overexpressed on the membrane of TV and suppression of Bip/Grp78 blocked TV formation. In addition, suppression of Bip/Grp78-enhanced CsA-induced cell death and CsA-induced TV formation and Bip/Grp78 overexpression had a characteristic striped pattern in the tubulointerstitium. In summary, we demonstrate that CsA-induced TV was a potentially reversible process in which Bip/Grp78 overexpression is essential for TV formation. It is possible that Bip/Grp78 expression and TV formation may be involved in cellular defense mechanism against CsA nephrotoxicity.

Journal Section:
Original Paper
Keywords:
Cyclosporine, ER stress, Bip/Grp78
1.
Sis B, Einecke G, Chang J, et al: Cluster analysis of lesions in nonselected kidney transplant biopsies: microcirculation changes, tubulointerstitial inflammation and scarring. Am J Transplant 2010;10:421.
[PubMed]
https://doi.org/10.1111%2Fj.1600-6143.2009.02938.x
2.
Liptak P, Ivanyi B: Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts. Nat Clin Pract Nephrol 2006;2:398-404.
[PubMed]
https://doi.org/10.1038%2Fncpneph0225
3.
Mihatsch MJ, Ryffel B, Hermle M, Brunner FP, Thiel G: Morphology of cyclosporine nephrotoxicity in the rat. Clin Nephrol 1986;25(suppl 1):S2-S8.
[PubMed]
4.
Prevot A, Semama DS, Justrabo E, Guignard JP, Escousse A, Gouyon JB: Acute cyclosporine A-induced nephrotoxicity: a rabbit model. Pediatr Nephrol 2000;14:370-375.
[PubMed]
https://doi.org/10.1007%2Fs004670050777
5.
Bredesen DE, Rao RV, Mechlen P: Cell death in the nervous system. Nature 2006;443:796-802.
[PubMed]
https://doi.org/10.1038%2Fnature05293
6.
Young J, Agashe V, Siegers K, Hartl U: Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 2004;5:5781-5791.
https://doi.org/10.1038%2Fnrm1492
7.
Sitia R, Braakman R: Quality control in the endoplasmic reticulum protein factory. Nature 2003;426:891-894.
[PubMed]
https://doi.org/10.1038%2Fnature02262
8.
Pallet N, Bouver N, Bendjallabah A, et al: Cyclosporine-induced endoplasmic reticulum stress trigger tubular phenotypic changes and death. Am J Transplant 2008;8:2283-2296.
[PubMed]
https://doi.org/10.1111%2Fj.1600-6143.2008.02396.x
9.
Sitia R, Braakman R: Quality control in the endoplasmic reticulum protein factory. Nature 2003;426:891-894.
[PubMed]
https://doi.org/10.1038%2Fnature02262
10.
Scheuner D, Song B, McEwen E, et al: Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 2001;7:1165-1176.
[PubMed]
https://doi.org/10.1016%2FS1097-2765%2801%2900265-9
11.
Bertolotti A, Zhang Y, Hendershot LM, Har-ding H, Ron D: Dynamic interaction of Bip and ER stress transducers in the unfolded protein response. Nat Cell Biol 2000;2:328-332.
12.
Bradshaw R, Dennis E (eds): Handbook of Cell Signaling. New York, Academic Press Elsevier Science, 2003, vol 3, pp 269-275.
13.
Vemba ST, Brodsy JL, Shruthi SV: One step a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 2008;9:944-956.
[PubMed]
https://doi.org/10.1038%2Fnrm2546
14.
Morris JA, Dorner AJ, Edward CA, Hendershot LM, Kaufman J: Immunoglobulin binding protein function is required to protect cell from endoplasmic reticulum stress but is not required for the secretion of selective protein. J Biol Chem 1997;272:4327-4334.
[PubMed]
https://doi.org/10.1074%2Fjbc.272.7.4327
15.
Bertocchio JP, van Huyen JP, Moghrabi SE, Rieu P, Jaisser F: Beneficial effect of mineralcorticoid receptor antagonism in acute cyclosporine A nephrotoxicity. ASN 2010.
16.
Bobadilla NA, Gamba G: New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone. Am J Physiol Renal Physiol 2007;290:F2-F9.
https://doi.org/10.1152%2Fajprenal.00072.2007
17.
Naeans M, Kuyper DRJ, Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481-508.
[PubMed]
© 2013 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
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.
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 government 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.
2013
You do not currently have access to this content.