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NDT Advance Access originally published online on July 12, 2008
Nephrology Dialysis Transplantation 2008 23(12):4061-4069; doi:10.1093/ndt/gfn388
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The role of macrophage in the pathogenesis of chronic cyclosporine-induced nephropathy

Jung Yeon Ghee1, Dong He Han1, Hyun Kuk Song1, Wan Young Kim2, Su Hyun Kim1,3, Hye Eun Yoon1, Bum Soon Choi1, Yong Soo Kim1, Jin Kim2 and Chul Woo Yang1

1 Department of Internal Medicine 2 Department of Anatomy, Cell Death Disease Research Center, The Catholic University of Korea 3 Department of Internal Medicine, College of Medicine, Chungang University, Seoul, Korea

Correspondence and offprint requests to: Chul Woo Yang, Department of Internal Medicine, Kangnam St Mary's Hospital, College of Medicine, The Catholic University of Korea 505, Banpo-dong, Seocho-gu, Seoul 137-040, Korea. Tel: +82-2-590-2527; Fax: +82-2-536-0323; E-mail: yangch{at}catholic.ac.kr



  Abstract

Background. Macrophages play diverse roles in tissue injury. We evaluated their role in cyclosporine (CsA)-induced renal injury by depletion with liposomal clodronate (CL).

Methods. Male Sprague Dawley rats were treated with CsA with or without CL treatment for 28 days. We assessed responses from the pathology and by measuring renal functions and levels of a proinflammatory cytokine (osteopontin), a profibrotic cytokine (βig-h3), innate immune response markers (toll-like receptor 2 and MHC class II molecules), apoptotic cell death (deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling staining and caspase-3 expression) and oxidative stress (8-hydroxy-2'-deoxyguanosine, 8-OHdG).

Results. Macrophage depletion with CL improved not only renal function but also histopathology compared with the CsA-treated rats. Osteopontin and βig-h3 levels increased significantly in CsA-treated rat kidneys, but CL treatment decreased both markers. Enhanced innate immune response and apoptotic cell death in CsA-treated rat kidney were decreased with CL. The increased rates of urinary 8-OHdG excretion and the tubular expression of 8-OHdG produced by CsA treatment were reversed with CL treatment.

Conclusions. Thus, infiltrating macrophages were involved in both nonimmunologic and immunologic injury and led to apoptotic cell death in this rat model of chronic CsA nephropathy.

Keywords: clodronate; cyclosporine; macrophage; nephrotoxicity

Received for publication: 1. 5.08
Accepted in revised form: 19. 6.08


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