NDT Advance Access originally published online on May 16, 2006
Nephrology Dialysis Transplantation 2006 21(8):2085-2095; doi:10.1093/ndt/gfl209
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Original Articles: Experimental Nephrology
Protective role of L-2-oxothiazolidine-4-carboxylic acid in cisplatin-induced renal injury
1 Department of Internal Medicine, 2 Department of Pathology and 3 Department of Radiology, Renal Regeneration Laboratory, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Republic of Korea
Correspondence and offprint requests to: Sung Kwang Park, MD, Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju 561-712, Republic of Korea. Email: parksk{at}chonbuk.ac.kr
Background. Oxidative stress and inflammation are implicated in the pathogenesis of cisplatin-induced nephrotoxicity. L-2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug, and increases cellular glutathione (GSH). OTC is converted to cysteine by the intracellular enzyme, oxoprolinase. To date, the protective role of OTC on cisplatin-induced renal injury has not been investigated. The purpose of the present study was to examine the protective effect of OTC on cisplatin-induced renal injury and to examine the mechanism of its protection.
Methods. Mice were treated with cisplatin with or without administration of OTC. The generation of reactive oxygen species (ROS), expression of intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 were determined in the kidney using 2',7'-dichlorofluorescein diacetate, immunostaining or western blot analysis. Nuclear factor (NF)-
B activity, infiltration of F4/80-positive cells and apoptosis were also investigated in addition to renal function and histology using electrophoretic mobility shift assay, immunostaining, western blot analysis, uridine triphosphate (dUTP) nick-end labelling or periodic acid–Schiff staining. The effect of OTC on superoxide dismutase activity and GSH level in cisplatin-treated normal adult human kidney (HK-2) cells were measured using assay kits.
Results. The administration of OTC resulted in a significant reduction of cisplatin-induced ROS production, the p65 subunit of NF-B translocation into nucleus, expression of ICAM-1, caspase 3 activity, expression of MCP-1 and the infiltration of macrophages into renal tissue. OTC markedly ameliorated renal damage induced by cisplatin through antioxidant and anti-inflammatory effect.
Conclusions. These results suggest that OTC can be a potential therapeutic agent in cisplatin-induced renal injury through decreasing the ROS levels and activation of NF-B.
Keywords: cisplatin; L-2-oxothiazolidine-4-carboxylic acid; nuclear factor-B; oxidative stress
*The authors wish it to be known that, in their opinion, the first two authors contributed equally to this work.
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