肝再生增强因子对横纹肌溶解致大鼠急性肾损伤的保护作用及机制研究

Protective effects of augmenter of liver regeneration on rhabdomyolysis induced acute kidney injury in rats

摘要:

目的：探讨肝再生增强因子（augmenter of liver regeneration，ALR）对横纹肌溶解致大鼠急性肾损伤（acute kidney in－jury，AKI）的保护作用及机制。方法：采用双侧后腿肌内注射甘油（50%甘油生理盐水，10 mL/kg）制备AKI动物模型。SD大鼠随机分为3组，每组8只。分别为正常组、AKI组和AKI+ALR组，ALR采用重组人ALR（recombinant human ALR，rhALR）腹腔注射（100 mg/kg）。于实验第48小时检测各组肾组织匀浆中丙二醛（malondialdehyde，MDA）含量、超氧化物歧化酶（superoxide dismutase，SOD）活性和还原型谷胱甘肽（reduced glutathione，GSH）含量，常规生化法检测血肌酐（serum creatinine，Scr）、尿素氮（blood urea nitrogen，BUN）和肌酸激酶（creatine kinase，CK）水平，HE染色观察各组肾脏病理形态的改变，免疫组化检测肾组织增殖细胞核抗原（proliferating cell nuclear antigen，PCNA）的表达。结果：与正常组相比，AKI组Scr、BUN和CK水平明显上升（P=0.000），出现典型的肾小管损伤坏死、管型、间质水肿等结构异常，肾组织中SOD活性和GSH含量降低（P=0.000），MDA含量增高（P=0.000），肾组织PCNA的表达明显上升（P=0.000）；与AKI组相比，AKI+ALR组Scr、BUN和CK水平明显下降（P=0.000），肾小管损伤评分明显降低（P=0.000），肾组织中SOD活性和GSH含量增加，MDA含量下降（P=0.000），肾组织PCNA的表达明显增高，增生指数明显上升（P=0.000）。结论：ALR对横纹肌溶解致急性肾损伤有明显的保护作用，其机制与抑制肾脏氧化应激和促进肾小管上皮细胞增殖有关。

Abstract:

Objective：To determine whether augmenter of liver regeneration（ALR） attenuated acute kidney injury（AKI） in rats follow－ing intramuscular injection of glycerol and to investigate the possible mechanism. Methods：The therapeutic effect of recombinant hu－man ALR（rhALR，100 mg/kg） on AKI was investigated in a glycerol（50% glycerol saline，10 mL/kg）-induced rhabdomyolysis model of AKI in rats. Male sprague dawley rats were randomly assigned to normal，AKI，or AKI+ALR groups. Renal function，creatine kinase（CK） and renal histology were to checked to determine the extent of renal damage. The expression of proliferating cell nuclear anti－gen（PCNA） was assayed to evaluate cell proliferation. Malondialdehyde（MDA），superoxide dismutase（SOD） and reduced glutathione（GSH） activities were monitored to evaluate oxidative stress. Results：Glycerol treatment induced renal function impairment（BUN and Scr were both increased），CK increase and structural abnormalities including tubular necrosis，cast formation，brush border loss，and interstitial edema. SOD activity and GSH in the kidney decreased，while MDA in the kidney increased in AKI group. A compensatory increase of PCNA was detected in AKI group. ALR had no detectable effects on normal rat kidneys，but it significantly improved renal function and alleviated pathological damage and oxidative stress in glycerol induced acute injured kidneys（AKI+ALR groups）. Renal expression of PCNA also increased in AKI+ALR group compared with that of AKI group. Conclusion：ALR significantly attenuates glycerol-induced AKI. The renal protective effects are associated with the inhibition of oxidative stress and the promotion of renal tubular epithelial cell proliferation.