Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors

• Published in: Life sciences (1973) Vol. 88; no. 25; pp. 1142 - 1148
• Main Authors: Mitazaki, Satoru, Honma, Shigeyoshi, Suto, Miwako, Kato, Naho, Hiraiwa, Kouichi, Yoshida, Makoto, Abe, Sumiko
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 20.06.2011
• Subjects: 4-HNE; Acute Kidney Injury - chemically induced; Acute Kidney Injury - enzymology; Acute Kidney Injury - immunology; Acute Kidney Injury - pathology; Animals; Antineoplastic Agents - adverse effects; Antioxidants - metabolism; apoptosis; blood; Blotting, Western; caspase-3; chemotherapy; Cisplatin; Cisplatin - adverse effects; cox-2; Cyclooxygenase 2 - biosynthesis; IL-6 deficiency; Immunohistochemistry; interleukin-6; Interleukin-6 - genetics; Interleukin-6 - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mitogen-activated protein kinase; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - immunology; phosphorylation; prostaglandin synthase; proximal tubules; Renal failure; Reverse Transcriptase Polymerase Chain Reaction; superoxide dismutase; Up-Regulation; IL-6 deficiency; Oxidative stress; 4-HNE; cox-2; Cisplatin; Renal failure
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.04.016

Cisplatin, a major chemotherapeutic agent, accumulates in proximal tubules of the kidneys and causes acute renal failure dose-dependently. We previously reported that cisplatin induced more severe renal dysfunction in interleukin-6 (IL-6) knockout (IL-6 −/−) mice than in wild-type (WT) mice. Expression of a pro-apoptotic protein was significantly increased with cisplatin in IL-6 −/− mice compared to that in WT mice. IL-6, locally expressed in renal tubular cells after cisplatin administration, prevents the development of renal dysfunction at an early stage. In the present study, we focused on downstream signals of IL-6 and oxidative stress induced by cisplatin in order to evaluate the protective role of IL-6 in the development of acute renal failure. WT and IL-6 −/− mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. Blood and kidney samples were collected at 24 h and 72 h after cisplatin administration. The changes in expression of 4-hydroxy-2-nonenal protein (4-HNE, oxidative stress marker) and cyclooxygenase-2 (cox-2), activities of superoxide dismutases and caspase-3, and phosphorylation of extracellular signal-regulated kinase (ERK) were examined. Cisplatin increased the expression of 4-HNE and cox-2, and phosphorylation of ERK in IL-6 −/− mice than in WT mice. On the other hand, activity of superoxide dismutase, an anti-oxidative enzyme, was significantly decreased in the kidney obtained from IL-6 −/− mice after cisplatin administration. Our findings suggest that IL-6 plays a protective role in the development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors.