title: Beneficial Effects of Necrosis Modulator, Indole Derivative NecroX-7, on Renal Ischemia-Reperfusion Injury in Rats.
abstract: Renal ischemia-reperfusion injury (IRI) is involved in multiple diseases, such as kidney transplantation or contrast-induced nephropathy, and leads to acute kidney injury. However, there are no pharmacological agents available to prevent IRI. In this study, we investigated the effects of necroX-7 against renal IRI in a rat model. Seven-week-old male Sprague-Dawley rats were divided into four groups: saline-treated sham or IRI group, necroX-7-treated sham or IRI group. All animals had right nephrectomy and IRI was followed by reperfusion after clamping the left renal vessels for 35 minutes. NecroX-7 or saline was intravenously injected at 5 minutes before reperfusion. The effects of necroX-7 on IRI were evaluated using biochemical, histological, and molecular markers. The serum creatinine level was increased after IRI compared with sham. The necroX-7 significantly decreased creatinine level compared with the saline in IRI (1.36 ± 0.11 vs 2.35 ± 0.42 mg/dL; P < .05). An immunohistochemical study revealed that necroX-7 improved renal tubular injury, and attenuated 8-OHdG-positive cells (P < .001) and high-mobility group Box 1 protein (HMGB1) expression compared with saline treatment in IRI (P < .001). NecroX-7 significantly reduced monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor (TNF)-α, and interleukin (IL)-1ß in IRI (necroX-7-treated IRI vs saline-treated IRI rats; 1.73 ± 0.42 vs 7.23 ± 0.54-fold for MCP-1, P < .05; 0.79 ± 0.59 vs 3.72 ± 0.37-fold for TNF-α, P < .05; 0.50 ± 0.36 vs 2.43 ± 0.41-fold for IL-1ß, P < .001). In conclusion, necroX-7 improved renal dysfunction after IRI. These effects of necroX-7 occurred with the suppression of reactive oxygen species, HMGB1, and inflammatory responses. We suggest that necroX-7 has potential therapeutic benefits in renal IRI.
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: S A
authors.initials: SA
authors.lastname: Jin
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: S K
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Seo
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: K T
authors.initials: KT
authors.lastname: Ahn
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: D E
authors.initials: DE
authors.lastname: Choi
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: S W
authors.initials: SW
authors.lastname: Choi
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: I W
authors.initials: IW
authors.lastname: Seong
authors.affiliation: Department of Product Strategy and Development, LG Life Sciences Ltd, Seoul, Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea. Electronic address: jojeong@cnu.ac.kr.
authors.forename: J-O
authors.initials: JO
authors.lastname: Jeong
mesh_terms: D000818:Animals; D024243:HMGB1 Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000601:surgery; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D009336:Necrosis; D009392:Nephrectomy / Q000009:adverse effects; D009930:Organic Chemicals / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D053583:Interleukin-1beta; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C556282:necrox-7