TIM2 gene deletion results in susceptibility to cisplatin-induced kidney toxicity.
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.
Krishnamoorthy
Aparna
A
Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Clement
Matthew E
ME
O'Leary
Eileen
E
Bonventre
Joseph V
JV
Vaidya
Vishal S
VS
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007274:Injections, Intraperitoneal; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism
D000970:Antineoplastic Agents; D016207:Cytokines; D008565:Membrane Proteins; D012333:RNA, Messenger; C442242:Timd2 protein, mouse; D003404:Creatinine; D002945:Cisplatin