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目的探讨不同剂量重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)对大鼠肾脏缺血再灌注损伤(renal ischemia reperfusion injury,RIRI)的保护作用及其机制。方法将40只健康的雄性大鼠随机分为5组:假手术组(S组),缺血再灌注模型组(IR组),rhEPO大剂量治疗组(H组),rhEPO中剂量治疗组(M组),rhEPO小剂量治疗组(L组)。IR组、H组、M组、L组分别通过夹闭双侧肾动、静脉45 min,制作大鼠RIRI模型,H组、M组、L组于造模成功后分别按照5 000 IU/kg、3 000 IU/kg、1 000 IU/kg标准给予腹腔注射rhEPO。比色法测定血清肌酐(SCr)和尿素氮(BUN),免疫组化分析法测定血红素加氧酶-1(heme oxygenase-1,HO-1)、白细胞介素6(interleukin-6,IL-6),HE染色分析肾组织形态学变化。结果与S组比较,IR组大鼠SCr及BUN水平于缺血再灌注1 h即有显著上升(P<0.05),并且随着再灌注时间的延长逐渐升高。在各个再灌注时间点(1、6、12、24 h)上,H组、M组的SCr、BUN较IR组均有下降趋势,但以H组下降幅度最明显。L组与IR组相比较,肾功能无明显改善。至再灌注后24 h,BUN与SCr均未达峰值。IR组肾组织中IL-6、HO-1的表达明显高于S组。H组、M组中IL-6的水平均显著降低,HO-1水平升高,且与rhEPO的剂量相关,而L组与IR组相比无明显差异。IR主要累及肾小管上皮细胞。与IR组比较,S组可见正常大鼠肾小球及肾小管的组织形态结构,在各个时间点均未出现明显的组织坏死。结论rhEPO对RIRI有保护作用,且剂量越大,对缺血再灌注损伤的保护作用越明显。推测其保护机制可能与rhEPO抑制肾小管上皮细胞凋亡而减轻RIRI相关。
Objective To investigate the protective effect and mechanism of recombinant human erythropoietin (rhEPO) on renal ischemia reperfusion injury (RIRI) in rats. Methods Forty healthy male rats were randomly divided into five groups: sham operation group (S group), ischemia reperfusion model group (IR group), rhEPO high dose treatment group (H group), rhEPO medium dose treatment group M group), rhEPO low-dose treatment group (L group). RIRI models were made in IR, H, M and L groups by bilateral renal artery and vein occlusion for 45 min, respectively. Groups H, M and L were killed at 5 000 IU / kg , 3 000 IU / kg, 1 000 IU / kg standard intraperitoneal injection of rhEPO. Serum creatinine (SCr) and blood urea nitrogen (BUN) were measured by colorimetric method. The levels of heme oxygenase-1 (HO-1), interleukin-6 -6), HE staining analysis of renal morphological changes. Results Compared with group S, the level of SCr and BUN in IR group increased significantly 1 h after ischemia / reperfusion (P <0.05), and gradually increased with the reperfusion time prolonging. At each time point of reperfusion (1, 6, 12, 24 h), SCr and BUN in H group and M group decreased compared with IR group, but the most obvious decrease was in H group. L group compared with IR group, no significant improvement in renal function. 24 h after reperfusion, BUN and SCr did not reach the peak. The expression of IL-6 and HO-1 in IR group was significantly higher than that in S group. The levels of IL-6 in H group and M group were significantly decreased, the HO-1 level was increased, and the dose of rhEPO was related, while there was no significant difference between L group and IR group. IR mainly affects renal tubular epithelial cells. Compared with IR group, the histopathology of glomeruli and tubules of normal rats were observed in group S, and no obvious tissue necrosis occurred at all time points. Conclusion rhEPO has a protective effect on RIRI, and the greater the dose, the more obvious the protective effect on ischemia-reperfusion injury. It is speculated that its protective mechanism may be associated with rhEPO inhibition of renal tubular epithelial cell apoptosis and reduce RIRI.