α硫辛酸后处理对脓毒症大鼠急性肾损伤的影响及机制

Efficacy of α-Lipoic Acid Treatment on Sepsis-induced Acute Kidney Injury in Rats and Its Mechanisms

目的探讨α硫辛酸(ALA)后处理对脓毒症大鼠急性肾损伤的影响及其可能机制。方法 32只雄性SD大鼠随机分成4组:正常对照组(A组)、ALA后处理对照组(B组)、脓毒症组(C组)和脓毒症联合ALA后处理组(D组)。A、B 2组均行假手术,C、D 2组行盲肠结扎穿孔术(CLP)复制脓毒症模型。B、D 2组大鼠术后立即给予ALA 200 mg/kg灌胃。24 h后检测大鼠血清肌酐(SCr)、尿素氮(BUN)、肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6-)及白细胞介素1β(IL-1β)水平,肾组织行PAS染色观察病理学改变,免疫印迹法测定NF-κB相关蛋白表达。结果脓毒症可以诱发肾脏病理学改变,与A组相比,C组SCr和BUN含量分别增加了178%和66%(P<0.01),TNF-α、IL-6及IL-1β水平分别增加55%、114%和110%(P<0.01);同时NF-κB p65的磷酸化水平(144%)和细胞核内的表达(102%)显著增加(P<0.01),并IκBα的表达下降61%(P<0.01)。早期给予ALA可以明显改善上述变化,与C组相比,D组SCr和BUN含量分别下降了48%和26%(P<0.05),TNF-α、IL-6及IL-1β水平分别降低25%、37%和40%(P<0.05);同时NF-κB p65的磷酸化水平和细胞核内的表达显著减少41%和49%(P<0.05),IκBα的相对表达水平增加103%(P<0.05)。结论 ALA抑制NF-κB的活化,从而改善脓毒症相关急性肾损伤。

Objective To investigate the impact of α-lipoic acid （ALA） treatment on sepsis-induced acute kidney injury in rats and explore the mechanisms. Methods A total of 32 male SD rats were randomized into 4 groups ： normal control group （group A）, ALA- treated control group （group B ）, sepsis group （ group C ） and sepsis with ALA treated group （ group D）. Group A and B underwent sham operation, while CLP operations were conducted in group C and D. Rats in both group B and group D were then administered with 200 mg/kg ALA by oral gavage immediately after the surgical procedure. Twenty-four hours after the surgical procedure blood samples were obtained for the evaluation of creatinine, BUN, TNF-α, IL- 6 and IL-113. Rat kidneys were rapidly removed for PAS stain. Western blot was employed to determine the expression of NF-KB. Results Pathologi- cal changes of kidney were induced by sepsis and the level of creatinine, BUN, TNF-α, IL-6 and IL- 1[5 were significantly increased by 178%, 66%, 55%, 114% and 110% （P 〈 0.01 ）. respectively; simultaneously the phosphorylation and nuclear expression of NF- KB p65 in kidney tissues were significantly increased by 144% and 102% （P 〈 0.01 ）. Sepsis-induced acute kidney injury also significantly reduced the expression of IkBα by 61% （P 〈 0.01 ）. These changes were significantly suppressed by early ALA treatment. Compared with C group, the level of creatinine, BUN, TNF- or, IL-6 and IL- 1 [3 were significantly decreased by 48%, 26%, 25%, 37% and 40% （P 〈 0.05 ）, respectively, and the relative expression of IKBo~ was increased by 103% （P 〈 0.05 ）. Conclusion The present study demonstrated that ALA can suppress the activation of NF-KB, thus ameliorat- ing sepsis-related acute kidney injury.