Jin S A, Kim S K, Seo H J, Jeong J Y, Ahn K T, Kim J H, Choi D E, Park J H, Lee J H, Choi S W, Seong I W, Kim S H, Suh K S, Jeong J-O
Divison of Cardiology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
Division of Nephrology, Department of Internal Medicine, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Korea.
Transplant Proc. 2016 Jan-Feb;48(1):199-204. doi: 10.1016/j.transproceed.2015.12.018.
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.
肾缺血再灌注损伤（IRI）与多种疾病相关，如肾移植或造影剂所致肾病，并可导致急性肾损伤。然而，目前尚无预防IRI的药物。在本研究中，我们在大鼠模型中研究了necroX-7对肾IRI的影响。将7周龄雄性Sprague-Dawley大鼠分为四组：生理盐水处理的假手术组或IRI组、necroX-7处理的假手术组或IRI组。所有动物均行右肾切除术，在夹闭左肾血管35分钟后进行再灌注以诱导IRI。在再灌注前5分钟静脉注射necroX-7或生理盐水。使用生化、组织学和分子标志物评估necroX-7对IRI的影响。与假手术组相比，IRI后血清肌酐水平升高。与IRI组中的生理盐水相比，necroX-7显著降低了肌酐水平（1.36± 0.11 vs 2.35± 0.42 mg/dL；P <.05）。免疫组织化学研究显示，与IRI组中的生理盐水处理相比，necroX-7改善了肾小管损伤，并减少了8-羟基脱氧鸟苷（8-OHdG）阳性细胞（P <.001）和高迁移率族蛋白B1（HMGB1）的表达（P <.001）。necroX-7显著降低了IRI中的单核细胞趋化蛋白1（MCP-1）、肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β水平（necroX-7处理的IRI组与生理盐水处理的IRI组大鼠相比；MCP-1为1.73± 0.42 vs 7.23± 0.54倍，P <.05；TNF-α为0.79± 0.59 vs 3.72± 0.37倍，P <.05；IL-1β为0.50± 0.36 vs 2.43± 0.41倍，P <.001）。总之，necroX-7改善了IRI后的肾功能障碍。necroX-7的这些作用是通过抑制活性氧、HMGB1和炎症反应而发生的。我们认为necroX-7在肾IRI中具有潜在的治疗益处。
