title: Interleukin-6 plays a protective role in development of cisplatin-induced acute renal failure through upregulation of anti-oxidative stress factors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  WT and IL-6(-/-) mice were given either cisplatin (30 mg/kg) or saline intraperitoneally. Blood and kidney samples were collected at 24h 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Forensic Toxicology, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki 370-0033, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Mitazaki
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Honma
authors.forename: Miwako
authors.initials: M
authors.lastname: Suto
authors.forename: Naho
authors.initials: N
authors.lastname: Kato
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hiraiwa
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshida
authors.forename: Sumiko
authors.initials: S
authors.lastname: Abe
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D002945:Cisplatin / Q000009:adverse effects*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D015850:Interleukin-6; D051546:Cyclooxygenase 2; D002945:Cisplatin