Laboratory of Medical Research - LIM12, Nephrology Department, University of São Paulo School of Medicine, São Paulo, Brazil.
Laboratory of Medical Research - LIM12, Nephrology Department, University of São Paulo School of Medicine, São Paulo, Brazil.
Free Radic Biol Med. 2016 Dec;101:176-189. doi: 10.1016/j.freeradbiomed.2016.10.012. Epub 2016 Oct 18.
Acute kidney injury (AKI) is the most severe complication of rhabdomyolysis. Allopurinol (Allo), a xanthine oxidase inhibitor, has been in the spotlight in the last decade due to new therapeutic applications related to its potent antioxidant effect. The aim of this study was to evaluate the efficacy of Allo in the prevention and treatment of rhabdomyolysis-associated AKI.
Male Wistar rats were divided into five groups: saline control group; prophylactic Allo (300mg/L of drinking water, 7 days); glycerol (50%, 5ml/kg, IM); prophylactic Allo + glycerol; and therapeutic Allo (50mg/Kg, IV, 30min after glycerol injection) + glycerol.
Glycerol-injected rats showed markedly reduced glomerular filtration rate associated with renal vasoconstriction, renal tubular damage, increased oxidative stress, apoptosis and inflammation. Allo ameliorated all these alterations. We found 8-isoprostane-PGF (F2-IsoP) as a main factor involved in the oxidative stress-mediated renal vasoconstriction following rhabdomyolysis. Allo reduced F2-IsoP renal expression and restored renal blood flow. Allo also reduced oxidative stress in the damaged muscle, attenuated muscle lesion/inflammation and accelerated muscular recovery. Moreover, we showed new insights into the pathogenesis of rhabdomyolysis-associated AKI, whereas Allo treatment reduced renal inflammation by decreasing renal tissue uric acid levels and consequently inhibiting the inflammasome cascade.
Allo treatment attenuates renal dysfunction in a model of rhabdomyolysis-associated AKI by reducing oxidative stress (systemic, renal and muscular), apoptosis and inflammation. This may represent a new therapeutic approach for rhabdomyolysis-associated AKI - a new use for an old and widely available medication.
急性肾损伤（AKI）是横纹肌溶解症最严重的并发症。黄嘌呤氧化酶抑制剂别嘌醇（Allo）因其强大的抗氧化作用而在过去十年中受到新的治疗应用的关注。本研究旨在评估 Allo 在预防和治疗横纹肌溶解症相关 AKI 中的疗效。
雄性 Wistar 大鼠分为五组：生理盐水对照组；预防性 Allo（300mg/L 饮用水，7 天）；甘油（50%，5ml/kg，IM）；预防性 Allo+甘油；和治疗性 Allo（50mg/kg，IV，甘油注射后 30 分钟）+甘油。
甘油注射大鼠肾小球滤过率明显降低，伴有肾血管收缩、肾小管损伤、氧化应激增加、细胞凋亡和炎症。Allo 改善了所有这些改变。我们发现 8-异前列腺素-PGF（F2-IsoP）是横纹肌溶解后氧化应激介导的肾血管收缩的主要因素。Allo 降低了肾脏 F2-IsoP 的表达并恢复了肾血流量。Allo 还降低了受损肌肉中的氧化应激，减轻了肌肉损伤/炎症并加速了肌肉恢复。此外，我们对横纹肌溶解症相关 AKI 的发病机制有了新的认识，而 Allo 治疗通过降低肾脏组织尿酸水平并抑制炎症小体级联反应来减少肾脏炎症。
Allo 通过减少氧化应激（全身、肾脏和肌肉）、细胞凋亡和炎症来减轻横纹肌溶解症相关 AKI 模型中的肾功能障碍。这可能代表了一种新的治疗横纹肌溶解症相关 AKI 的方法——一种旧的、广泛可用的药物的新用途。
