Tim-1 promotes cisplatin nephrotoxicity

Am J Physiol Renal Physiol. 2011 Nov;301(5):F1098-104. doi: 10.1152/ajprenal.00193.2011. Epub 2011 Aug 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • Antibodies, Blocking / pharmacology
  • Antineoplastic Agents / toxicity*
  • Apoptosis
  • Caspase 3 / metabolism
  • Chemokines / biosynthesis
  • Cisplatin / toxicity*
  • Cytokines / biosynthesis
  • Hepatitis A Virus Cellular Receptor 1
  • Homeodomain Proteins / genetics
  • Immunohistochemistry
  • Kidney / pathology
  • Kidney Diseases / chemically induced*
  • Kidney Diseases / pathology
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects
  • Lymphocyte Activation / physiology
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / physiology
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction


  • Antibodies, Blocking
  • Antineoplastic Agents
  • Chemokines
  • Cytokines
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Homeodomain Proteins
  • Membrane Proteins
  • NF-kappa B
  • RNA, Messenger
  • TIM-4 protein, mouse
  • RAG-1 protein
  • Caspase 3
  • Cisplatin