Journal Article

TIM2 Gene Deletion Results in Susceptibility to Cisplatin-Induced Kidney Toxicity

Aparna Krishnamoorthy, Matthew E. Clement, Eileen O'leary, Joseph V. Bonventre and Vishal S. Vaidya

in Toxicological Sciences

Volume 118, issue 1, pages 298-306
Published in print November 2010 | ISSN: 1096-6080
Published online August 2010 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfq240
TIM2 Gene Deletion Results in Susceptibility to Cisplatin-Induced Kidney Toxicity

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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-1β, IL-6, and TGFβ, 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.

Keywords: TIM2; cisplatin; kidney; inflammation; apoptosis

Journal Article.  5219 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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