A pathophysiologic role for T lymphocytes in murine acute cisplatin nephrotoxicity

Manchang Liu, Chu Chun Chien, Melissa Burne-Taney, Roshni R. Molls, Lorraine C. Racusen, Robert B. Colvin, Hamid Rabb

Research output: Contribution to journalArticle

Abstract

Recent evidence supports a role for an inflammatory pathogenesis of cisplatin nephrotoxicity, but immune cell-mediated mechanisms in this disease are still largely unknown. The role for T lymphocytes on cisplatin-induced acute kidney injury was examined with C57BL/6 T cell-deficient (nu/nu) mice and CD4- or CD8-deficient mice and their wild-type (WT) littermates. All mice received a single dose of cisplatin at 40 mg/kg (intraperitoneally) and were followed up for 72 h. At 72 h after cisplatin administration, T cell-deficient mice had a marked attenuation in renal dysfunction (serum creatinine 3.2 ± 0.5 versus 0.8 ± 0.1 mg/dl; P = 0.007), kidney tubular injury (scores 1.44 ± 0.15 versus 0.22 ± 0.08; P < 0.0001), and survival. Adoptive transfer of T cells into nu/nu mice followed by cisplatin enhanced renal dysfunction and tubular injury. The increase in renal myeloperoxidase activity after cisplatin administration was blunted in nu/nu mice. Renal TNF-α, IL-1β, and keratinocyte-derived chemokine protein expression was increased in WT mice but not in nu/nu mice after cisplatin administration. T cell levels significantly increased in kidneys of WT mice after cisplatin administration as early as at 1 h, peaked at 12 h, and declined by 24 h. CD4- and, to a lesser degree, CD8-deficient mice were relatively protected from cisplatin-induced mortality and renal dysfunction compared with WT mice. These data demonstrate that T lymphocytes are direct mediators of experimental cisplatin nephrotoxicity. Targeting T lymphocytes could lead to improved ways to administer cisplatin safely to cancer patients.

Original languageEnglish (US)
Pages (from-to)765-774
Number of pages10
JournalJournal of the American Society of Nephrology
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2006

ASJC Scopus subject areas

  • Nephrology

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