title: Tim-1 promotes cisplatin nephrotoxicity.
abstract: Nephrotoxicity is a frequent complication of cisplatin-based chemotherapy, in which T cells are known to promote acute kidney injury. In this study, we examined the role of T cell immunoglobulin mucin 1 (Tim-1) in cisplatin-induced acute kidney injury using an inhibitory anti-Tim-1 antibody. Tim-1 acts to modulate T cell responses, but it is also expressed by damaged proximal tubules in the kidney, where it is known as kidney injury molecule-1 (Kim-1). Anti-Tim-1 antibodies attenuated cisplatin nephrotocity, with less histologic damage, improved renal function, and fewer leukocytes infiltrating the kidney compared with control antibody-treated mice. Renal NF-κB activation and apoptosis were reduced, and proinflammatory renal cytokine and chemokine mRNA expression was decreased. Renal Kim-1 expression was reduced, consistent with the diminished kidney injury after anti-Tim-1 antibody treatment. Furthermore, anti-Tim-1 antibodies reduced early systemic CD4+ and CD8+ T cell activation, apoptosis, and cytokine production. To determine whether the protective actions of anti-Tim-1 antibodies were due to effects on renal tubular cells, cisplatin nephrotoxicity was studied in Rag1(-/-) mice. Anti-Tim-1 antibodies did not affect renal dysfunction or histologic damage in Rag1(-/-) mice, showing that the benefits of inhibiting Tim-1 come from T cell effects. As Tim-1 plays an important role in promoting cisplatin nephrotoxicity, inhibiting Tim-1 may be a therapeutic strategy to prevent cisplatin-induced acute kidney injury.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nozaki
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins / Q000235:genetics; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects; D008213:Lymphocyte Activation / Q000502:physiology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D019138:Antibodies, Blocking; D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018398:Homeodomain Proteins; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C500399:TIM-4 protein, mouse; C064658:RAG-1 protein; D053148:Caspase 3; D002945:Cisplatin