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.