Interleukin-6 deficiency accelerates cisplatin-induced acute renal failure but not systemic injury

• Published in: Toxicology (Amsterdam) 2009-11, Vol.265 (3), p.115-121
• Main Authors: Mitazaki, S, Kato, N, Suto, M, Hiraiwa, K, Abe, S
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - pathology; Animals; Antineoplastic Agents - toxicity; bcl-2-Associated X Protein - biosynthesis; bcl-2-Associated X Protein - genetics; bcl-X Protein - biosynthesis; bcl-X Protein - genetics; Blood Urea Nitrogen; Cisplatin; Cisplatin - toxicity; Emergency; Gene Expression Profiling; Heme Oxygenase-1 - metabolism; IL-6 deficiency; Immunohistochemistry; Interleukin-6 - blood; Interleukin-6 - deficiency; Interleukin-6 - genetics; Interleukin-6 - metabolism; Kidney Tubules, Proximal - drug effects; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Proto-Oncogene Proteins c-fos - metabolism; Renal failure; RNA, Messenger - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - biosynthesis; Suppressor of Cytokine Signaling Proteins - genetics; Survival Analysis; Time Factors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/j.tox.2009.10.005

Abstract Cisplatin (CDDP), a major chemotherapeutic agent used to treat solid tumors, is known to induce acute renal failure (ARF). The progression of tissue injury involves the coordination of inflammatory and repair responses. Interleukin-6 (IL-6) has been suggested to modulate inflammatory and repair processes in various tissue injuries. In this study, we analyzed IL-6 regulation during CDDP-induced ARF in wild-type (WT) mice and determined the pathological role of IL-6 using IL-6 knockout (−/− ) mice. A correlation between increase in serum IL-6 level and blood urea nitrogen level was found in WT mice. Renal IL-6 expression in most proximal tubular cells and suppressor of cytokine signaling 3 (SOCS3) gene expression significantly increased in WT mice after administration of CDDP, suggesting active IL-6 signaling during CDDP-induced ARF development. Interestingly, renal dysfunction occurred soon after administration of CDDP and became more severe in IL-6−/− mice than that in WT mice. In contrast, the survival rate of IL-6−/− mice (50% at 8 days) was better than that of WT mice (10%). Induction levels of proapoptotic Bcl-2 associated X protein (Bax) in renal proximal tubular cells was significantly higher in IL-6−/− mice than in WT mice at 24 h after CDDP injection. Levels of antiapoptotic proteins, Bcl-2 and Bcl-extra large (Bcl-xL ), in IL-6−/− groups were significantly higher than those in CDDP-treated WT groups throughout the experimental period. Bax might contribute to the development of CDDP-induced ARF at 24 h; however, high expression levels of Bcl-xL and Bcl-2 might overcome the proapoptosis signaling at 72 h in IL-6−/− mice. These results indicated that local and systemic elevation of IL-6 contributes to the development of CDDP-induced ARF and that IL-6 produced in renal tubular cells prevents progression of ARF at the early stage. IL-6 deficiency accelerates CDDP-induced ARF but not development of systemic injury.