Protective role of L-2-oxothiazolidine-4-carboxylic acid in cisplatin-induced renal injury.
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)-kappaB 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-kappaB 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-kappaB.
Lee
Sik
S
Department of Internal Medicine, Chonbuk National University Medical School, 634-18, Keum-Am Dong, Jeonju 561-712, Republic of Korea.
Moon
Sang-Ok
SO
Kim
Won
W
Sung
Mi Jeong
MJ
Kim
Duk Hoon
DH
Kang
Kyung Pyo
KP
Jang
Yong Bum
YB
Lee
Jung Eun
JE
Jang
Kyu Yun
KY
Lee
Sang Yong
SY
Park
Sung Kwang
SK
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000378:metabolism; D000975:Antioxidants / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line / Q000737:chemistry / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D002945:Cisplatin / Q000633:toxicity*; D003553:Cystine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007668:Kidney / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D007687:Kidney Tubules, Proximal / Q000166:cytology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D021381:Protein Transport; D011752:Pyroglutamate Hydrolase / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D053778:Thiazolidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000943:Antigens, Differentiation; D000975:Antioxidants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C090509:Icam1 protein, mouse; D011355:Prodrugs; C498144:Rela protein, mouse; D053778:Thiazolidines; D051996:Transcription Factor RelA; C036763:monocyte-macrophage differentiation antigen; D018799:Intercellular Adhesion Molecule-1; D003553:Cystine; D013482:Superoxide Dismutase; D053148:Caspase 3; D011752:Pyroglutamate Hydrolase; D005978:Glutathione; D002945:Cisplatin; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid