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Toxicol Sci ; 118(1): 298-306, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20702592

ABSTRACT

T-cell Immunoglobulin and Mucin domain 2 (TIM2) belongs to the receptor family of cell surface molecules expressed on kidney, liver, and T cells. Previous studies have revealed that TIM2-deficient mice (TIM2(-/-)) are more susceptible to the Th2-mediated immune response in an airway inflammation model. Here, we investigated the phenotypic response of TIM2(-/-) mice to cisplatin-induced kidney toxicity. A lethality study in male BALB/c wild-type (TIM2(+/+)) and TIM2(-/-) mice, administered with 20 mg/kg cisplatin ip, resulted in 80% mortality of TIM2(-/-) mice as compared with 30% mortality in the TIM2(+/+) group by day 5. The TIM2(-/-) mice showed approximately fivefold higher injury as estimated by blood urea nitrogen and serum creatinine at 48 h that was confirmed by significantly increased proximal tubular damage assessed histologically (H & E staining). A significantly higher expression of Th2-associated cytokines, TNF-α, IL-1ß, IL-6, and TGFß, with a significant reduction of Th1-associated cytokines, RANTES and MCP-1, by 72 h was observed in the TIM2(-/-) mice as compared with TIM2(+/+) mice. A higher baseline protein expression of caspase-3 (approximately twofold) coupled with an early onset of p53 protein activation by 48 h resulted in an increased apoptosis by 48-72 h in TIM2(-/-) compared with TIM2(+/+). In conclusion, the increased expression of the proinflammatory and proapoptotic genes, with a higher number of apoptotic cells, and a pronounced increase in injury and mortality of the TIM2-deficient mice collectively suggest a protective role of TIM2 in cisplatin-induced nephrotoxicity.


Subject(s)
Antineoplastic Agents/toxicity , Cisplatin/toxicity , Gene Deletion , Kidney Diseases/chemically induced , Kidney Diseases/genetics , Membrane Proteins/genetics , Animals , Apoptosis/drug effects , Blood Urea Nitrogen , Creatinine/blood , Cytokines/metabolism , Gene Expression , Genetic Predisposition to Disease , Injections, Intraperitoneal , Kidney Diseases/pathology , Longevity/drug effects , Male , Membrane Proteins/deficiency , Mice , Mice, Inbred BALB C , Mice, Knockout , RNA, Messenger/metabolism
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