Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun St., Charleston, SC 29425, USA.
J Pharmacol Exp Ther. 2012 Apr;341(1):126-36. doi: 10.1124/jpet.111.190249. Epub 2012 Jan 6.
Acute kidney injury (AKI) is a common and potentially life-threatening complication after ischemia/reperfusion and exposure to nephrotoxic agents. In this study, we examined the efficacy and mechanism(s) of suramin in promoting recovery from glycerol-induced AKI, a model of rhabdomyolysis-induced AKI. After intramuscular glycerol injection (10 ml of 50% glycerol per kilogram) into male Sprague-Dawley rats, serum creatinine maximally increased at 24 to 72 h and then decreased at 120 h. Creatinine clearance (CrCl) decreased 75% at 24 to 72 h and increased at 120 h. Suramin (1 mg/kg i.v.) administered 24 h after glycerol accelerated recovery of renal function as demonstrated by increased CrCl, decreased renal kidney injury molecule-1, and improved histopathology 72 h after glycerol injection. Suramin treatment decreased interleukin-1β (IL-1β) mRNA, transforming growth factor-β(1) (TGF-β(1)), phospho-p65 of nuclear factor-κB (NF-κB), and cleaved caspase-3 at 48 h compared with glycerol alone. Suramin treatment also decreased glycerol-induced activation of intracellular adhesion molecule-1 (ICAM-1) and leukocyte infiltration at 72 h. Urinary/renal neutrophil gelatinase-associated lipocalin 2 (NGAL) levels, hemeoxygenase-1 expression, and renal cell proliferation were increased by suramin compared with glycerol alone at 72 h. Mechanistically, suramin decreases early glycerol-induced proinflammatory (IL-1β and NF-κB) and growth inhibitory (TGF-β(1)) mediators, resulting in the prevention of late downstream inflammatory effects (ICAM-1 and leukocyte infiltration) and increasing compensatory nephrogenic repair. These results support the hypothesis that delayed administration of suramin is effective in abrogating apoptosis, attenuating inflammation, and enhancing nephrogenic repair after glycerol-induced AKI.
急性肾损伤（AKI）是缺血/再灌注和接触肾毒性药物后常见且潜在威胁生命的并发症。在这项研究中，我们研究了苏拉明促进甘油诱导的 AKI （横纹肌溶解诱导的 AKI 模型）恢复的功效和机制。雄性 Sprague-Dawley 大鼠肌肉内注射甘油（每公斤 10 毫升 50%甘油）后，血清肌酐在 24 至 72 小时内最大增加，然后在 120 小时内降低。肌酐清除率（CrCl）在 24 至 72 小时降低 75%，在 120 小时增加。甘油注射后 24 小时给予苏拉明（1mg/kg 静脉内）可加速肾功能恢复，表现为 CrCl 增加、肾损伤分子-1 减少以及甘油注射后 72 小时组织病理学改善。与单独甘油处理相比，苏拉明处理在 48 小时时降低白细胞介素-1β（IL-1β）mRNA、转化生长因子-β1（TGF-β1）、核因子-κB（NF-κB）磷酸化 p65 和切割的半胱天冬酶-3。苏拉明处理还可降低甘油诱导的细胞间黏附分子-1（ICAM-1）和白细胞浸润在 72 小时时的激活。与单独甘油处理相比，苏拉明处理在 72 小时时增加尿/肾中性粒细胞明胶酶相关脂质运载蛋白 2（NGAL）水平、血红素加氧酶-1 表达和肾细胞增殖。从机制上讲，苏拉明降低了早期甘油诱导的促炎（IL-1β和 NF-κB）和生长抑制（TGF-β1）介质，从而防止了晚期下游炎症效应（ICAM-1 和白细胞浸润）并增加了代偿性肾修复。这些结果支持这样的假说，即延迟给予苏拉明可有效阻断甘油诱导的 AKI 后的细胞凋亡、减轻炎症和增强肾发生修复。
