促红细胞生成素预处理对缺血性急性肾衰竭的保护作用及机制
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摘要
目的
研究重组人促红细胞生成素预处理对缺血性急性肾衰竭的保护作用并探讨其可能的作用机制。
方法
通过缺血再灌注损伤法建立在体大鼠缺血性急性肾衰竭模型,雄性成年SD大鼠48只随机分为4组,每组12只,缺血前及再灌注后各6只。假手术组大鼠单纯切除右肾,未行左肾缺血再灌注;缺血组大鼠行右肾切除,左肾缺血45 min再灌注24 h;促红素组大鼠亦单纯切除右肾,于术前24 h腹腔注射重组人促红细胞生成素3000 U/kg,但未行左肾缺血再灌注;促红素缺血组大鼠于缺血前24 h腹腔注射重组人促红细胞生成素3000 U/kg,行右肾切除,左肾缺血45 min再灌注24 h。假手术组及缺血组分别于术前24 h以生理盐水1.5 ml/kg腹腔注射。分别于缺血前及再灌注后测定血肌酐和尿素氮值,用HE染色及paller法肾小管评分观察肾组织损伤形态学改变,采用TUNEL法检测肾小管上皮细胞凋亡。分别于大鼠肾缺血前、缺血再灌注后取肾组织标本,采用Western blot法半定量分析促红细胞生成素对缺血性急性肾衰竭大鼠肾组织中抗凋亡因子Bcl-2及半胱天冬蛋白酶Caspase-3的蛋白表达的影响。
结果
肾功能结果:与假手术组(Scr 52.38±6.68,BUN 4.71±0.93)比较,再灌注后缺血组(Scr 353.20±34.34,BUN 41.25±4.10)、促红素缺血组(Scr 251.80±37.66,BUN 25.67±3.10)血肌酐、尿素氮明显升高(P﹤0.05);与缺血组(Scr 353.20±34.34,BUN 41.25±4.10)比较,促红素缺血组(Scr 251.80±37.66,BUN 25.67±3.10)血肌酐、尿素氮水平下降(P﹤0.05)。缺血前各组血肌酐、尿素氮差异无统计学意义。
肾组织形态学结果:与假手术组(19.33±3.33)比较,缺血组(250.67±23.96)及促红素缺血组(135.33±11.69)肾小管损伤明显、肾小管paller评分升高(P﹤0.05);与缺血组(250.67±23.96)比较,促红素缺血组(135.33±11.69)肾小管损伤减轻、肾小管paller评分下降(P﹤0.05)。
TUNEL染色结果:与假手术组[(1.17±0.48)%]比较,缺血组[(24.58±4.39)%]及促红素缺血组[(8.52±2.06)%] TUNEL凋亡指数增加(P﹤0.05);与缺血组[(24.58±4.39)%]比较,促红素缺血组[(8.52±2.06)%] TUNEL凋亡指数下降(P﹤0.05)。
缺血前各组Western blot结果:与假手术组(55.17±7.76)比较,促红素组(135.00±9.89)及促红素缺血组(133.05±8.78) Bcl-2蛋白表达上调(P﹤0.05),各组Caspase-3蛋白表达在缺血前差异无统计学意义。
再灌注后各组Western blot结果:与假手术组(Bcl-2,52.93±7.13,Caspase-3,18.53±1.86)比较,缺血组(28.12±6.49) Bcl-2蛋白表达下调(P﹤0.05),促红素组(133.08±8.92)、促红素缺血组(86.00±7.99) Bcl-2蛋白表达上调(P﹤0.05),缺血组(55.62±2.90)、促红素缺血组(45.77±2.08) Caspase-3蛋白表达上调(P﹤0.05);与缺血组(Bcl-2,28.12±6.49,Caspase-3,55.62±2.90)比较,促红素缺血组Bcl-2蛋白(86.00±7.99)表达上调,Caspase-3蛋白(45.77±2.08)表达下调(P﹤0.05)。
各组缺血前与再灌注后Western blot结果:与缺血前比较,缺血组、促红素缺血组缺血再灌注后Bcl-2蛋白表达下调(P﹤0.05),假手术组、促红素组缺血再灌注前后Bcl-2蛋白表达差异无统计学意义;缺血组、促红素缺血组再灌注后Caspase-3蛋白表达上调(P﹤0.05),假手术组、促红素组缺血再灌注前后Caspase-3蛋白表达差异无统计学意义。
结论
促红细胞生成素预处理对缺血性急性肾衰竭具有保护作用,其作用机制可能同上调缺血前Bcl-2蛋白的表达,减弱由缺血再灌注引起Bcl-2蛋白表达的下调,降低再灌注后Caspase-3蛋白表达的上调幅度,减轻肾小管上皮细胞凋亡有关。
Objective
To investigate the effect of preconditioning with recombinant human erythropoietin (rhEPO) on an in vivo rat model of ischemic acute renal failure and the possible mechanisms.
Methods
The model of ischemic acute renal failure was established by in vivo rat ischemia/reperfusion (I/R) injury. 48 male Sprague–Dawley rats were randomly allocated into four groups (12 per group, 6 before ischemia and 6 after reperfusion). (I) sham group, in which rats were right nephrectomy without left renal ischemia/reperfusion; (II) I/R group, in which rats were right nephrectomy and clamping on the left renal pedicle for 45 min and reperfusion for 24 h; (III) EPO group, in which rats were also right nephrectomy without ischemia/reperfusion and administered EPO (3000 U/kg, i.p) 24 h prior to laparotomy. (IV) EPO + I/R group, in which rats were administered EPO (3000 U/kg, i.p.) 24 h prior to I/R, then right nephrectomy and clamping on the left renal pedicle for 45 min and reperfusion for 24 h. The sham and I/R group were administered saline (1.5 ml/kg, i.p) 24 h prior to laparotomy respectively. Before ischemia and after 24 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading (H E staining). Apoptosis was assessed by the TUNEL method and morphological criteria (paller score). Expression of Bcl-2 and Casepase-3 was also evaluated by Western blot.
Results
Renal function: High levels of serum creatinine and blood urea in I/R (Scr 353.20±34.34, BUN 41.25±4.10) and EPO + I/R (Scr 251.80±37.66, BUN 25.67±3.10) group were identified at 24 h after ischemia (P<0.05 versus sham Scr 52.38±6.68, BUN 4.71±0.93). The EPO + I/R (Scr 251.80±37.66, BUN 25.67±3.10) group had significantly lower serum creatinine and blood urea levels (P<0.05 versus I/R Scr 353.20±34.34, BUN 41.25±4.10). There was no significant difference between Groups before ischemia.
Renal morphological: Compared with sham group (19.33±3.33), I/R (250.67±23.96) and EPO + I/R (135.33±11.69) group developed marked tubula structural damage and higher paller scores (P<0.05) whereas significantly less tubular damage and lower paller scores were observed in EPO + I/R (135.33±11.69) group compared with I/R (250.67±23.96) group (P<0.05).
TUNEL assay: Compared with sham [(1.17±0.48)%] group, I/R [(24.58±4.39)%] and EPO+I/R [(8.52±2.06)%] group caused an increase in TUNEL-positive cells (P<0.05), compared with I/R [(24.58±4.39)%] group, EPO+I/R [(8.52±2.06)%] group TUNEL- positive cells were decressed (P<0.05).
Before ischemia: Up-regulation of Bcl-2 in the tubular epithelial cells was observed in EPO (135.00±9.89) and EPO + I/R (133.05±8.78) group compared with sham (55.17±7.76) group (P<0.05). Casepase-3 was no significant difference between Groups before ischemia.
After reperfusion: Diminished expression of Bcl-2 in I/R (28.12±6.49) group and up-regulation of Bcl-2 in EPO (133.08±8.92) and EPO + I/R (86.00±7.99) group were observed compared with sham (52.93±7.13) group (P<0.05), up-regulation of Casepase-3 in I/R (55.62±2.90) and EPO + I/R (45.77±2.08) group was observed compared with sham (18.53±1.86) group (P<0.05). Up-regulation of Bcl-2 and decreased expression of casepase-3 in EPO + I/R (Bcl-2, 86.00±7.99, Caspase-3, 45.77±2.08) group were observed compared with I/R (Bcl-2, 28.12±6.49, Caspase-3, 55.62±2.90) group (P<0.05).
Compared with before ischemia, Bcl-2 decreased and Casepase-3 incresed in I/R and EPO + I/R group after reperfusion (P<0.05), there was no significant difference between sham and EPO Group.
Conclusion
The results indicate that erythropoietin has protective effects on ischemic acute renal failure, the mechanisms seems to be associated with its amelioration of renal tubular epithelial cell apoptosis by up-regulation the anti-apoptosis protein Bcl-2 before ischemia which attenuated the diminished expression of Bcl-2 and decreased the up-regulation of protein Caspase-3 after ischemia/reperfusion.
研究重组人促红细胞生成素预处理对缺血性急性肾衰竭的保护作用并探讨其可能的作用机制。
方法
通过缺血再灌注损伤法建立在体大鼠缺血性急性肾衰竭模型,雄性成年SD大鼠48只随机分为4组,每组12只,缺血前及再灌注后各6只。假手术组大鼠单纯切除右肾,未行左肾缺血再灌注;缺血组大鼠行右肾切除,左肾缺血45 min再灌注24 h;促红素组大鼠亦单纯切除右肾,于术前24 h腹腔注射重组人促红细胞生成素3000 U/kg,但未行左肾缺血再灌注;促红素缺血组大鼠于缺血前24 h腹腔注射重组人促红细胞生成素3000 U/kg,行右肾切除,左肾缺血45 min再灌注24 h。假手术组及缺血组分别于术前24 h以生理盐水1.5 ml/kg腹腔注射。分别于缺血前及再灌注后测定血肌酐和尿素氮值,用HE染色及paller法肾小管评分观察肾组织损伤形态学改变,采用TUNEL法检测肾小管上皮细胞凋亡。分别于大鼠肾缺血前、缺血再灌注后取肾组织标本,采用Western blot法半定量分析促红细胞生成素对缺血性急性肾衰竭大鼠肾组织中抗凋亡因子Bcl-2及半胱天冬蛋白酶Caspase-3的蛋白表达的影响。
结果
肾功能结果:与假手术组(Scr 52.38±6.68,BUN 4.71±0.93)比较,再灌注后缺血组(Scr 353.20±34.34,BUN 41.25±4.10)、促红素缺血组(Scr 251.80±37.66,BUN 25.67±3.10)血肌酐、尿素氮明显升高(P﹤0.05);与缺血组(Scr 353.20±34.34,BUN 41.25±4.10)比较,促红素缺血组(Scr 251.80±37.66,BUN 25.67±3.10)血肌酐、尿素氮水平下降(P﹤0.05)。缺血前各组血肌酐、尿素氮差异无统计学意义。
肾组织形态学结果:与假手术组(19.33±3.33)比较,缺血组(250.67±23.96)及促红素缺血组(135.33±11.69)肾小管损伤明显、肾小管paller评分升高(P﹤0.05);与缺血组(250.67±23.96)比较,促红素缺血组(135.33±11.69)肾小管损伤减轻、肾小管paller评分下降(P﹤0.05)。
TUNEL染色结果:与假手术组[(1.17±0.48)%]比较,缺血组[(24.58±4.39)%]及促红素缺血组[(8.52±2.06)%] TUNEL凋亡指数增加(P﹤0.05);与缺血组[(24.58±4.39)%]比较,促红素缺血组[(8.52±2.06)%] TUNEL凋亡指数下降(P﹤0.05)。
缺血前各组Western blot结果:与假手术组(55.17±7.76)比较,促红素组(135.00±9.89)及促红素缺血组(133.05±8.78) Bcl-2蛋白表达上调(P﹤0.05),各组Caspase-3蛋白表达在缺血前差异无统计学意义。
再灌注后各组Western blot结果:与假手术组(Bcl-2,52.93±7.13,Caspase-3,18.53±1.86)比较,缺血组(28.12±6.49) Bcl-2蛋白表达下调(P﹤0.05),促红素组(133.08±8.92)、促红素缺血组(86.00±7.99) Bcl-2蛋白表达上调(P﹤0.05),缺血组(55.62±2.90)、促红素缺血组(45.77±2.08) Caspase-3蛋白表达上调(P﹤0.05);与缺血组(Bcl-2,28.12±6.49,Caspase-3,55.62±2.90)比较,促红素缺血组Bcl-2蛋白(86.00±7.99)表达上调,Caspase-3蛋白(45.77±2.08)表达下调(P﹤0.05)。
各组缺血前与再灌注后Western blot结果:与缺血前比较,缺血组、促红素缺血组缺血再灌注后Bcl-2蛋白表达下调(P﹤0.05),假手术组、促红素组缺血再灌注前后Bcl-2蛋白表达差异无统计学意义;缺血组、促红素缺血组再灌注后Caspase-3蛋白表达上调(P﹤0.05),假手术组、促红素组缺血再灌注前后Caspase-3蛋白表达差异无统计学意义。
结论
促红细胞生成素预处理对缺血性急性肾衰竭具有保护作用,其作用机制可能同上调缺血前Bcl-2蛋白的表达,减弱由缺血再灌注引起Bcl-2蛋白表达的下调,降低再灌注后Caspase-3蛋白表达的上调幅度,减轻肾小管上皮细胞凋亡有关。
Objective
To investigate the effect of preconditioning with recombinant human erythropoietin (rhEPO) on an in vivo rat model of ischemic acute renal failure and the possible mechanisms.
Methods
The model of ischemic acute renal failure was established by in vivo rat ischemia/reperfusion (I/R) injury. 48 male Sprague–Dawley rats were randomly allocated into four groups (12 per group, 6 before ischemia and 6 after reperfusion). (I) sham group, in which rats were right nephrectomy without left renal ischemia/reperfusion; (II) I/R group, in which rats were right nephrectomy and clamping on the left renal pedicle for 45 min and reperfusion for 24 h; (III) EPO group, in which rats were also right nephrectomy without ischemia/reperfusion and administered EPO (3000 U/kg, i.p) 24 h prior to laparotomy. (IV) EPO + I/R group, in which rats were administered EPO (3000 U/kg, i.p.) 24 h prior to I/R, then right nephrectomy and clamping on the left renal pedicle for 45 min and reperfusion for 24 h. The sham and I/R group were administered saline (1.5 ml/kg, i.p) 24 h prior to laparotomy respectively. Before ischemia and after 24 h of reperfusion, the renal dysfunction and injury was assessed by measurement of serum biochemical markers (urea, creatinine) and histological grading (H E staining). Apoptosis was assessed by the TUNEL method and morphological criteria (paller score). Expression of Bcl-2 and Casepase-3 was also evaluated by Western blot.
Results
Renal function: High levels of serum creatinine and blood urea in I/R (Scr 353.20±34.34, BUN 41.25±4.10) and EPO + I/R (Scr 251.80±37.66, BUN 25.67±3.10) group were identified at 24 h after ischemia (P<0.05 versus sham Scr 52.38±6.68, BUN 4.71±0.93). The EPO + I/R (Scr 251.80±37.66, BUN 25.67±3.10) group had significantly lower serum creatinine and blood urea levels (P<0.05 versus I/R Scr 353.20±34.34, BUN 41.25±4.10). There was no significant difference between Groups before ischemia.
Renal morphological: Compared with sham group (19.33±3.33), I/R (250.67±23.96) and EPO + I/R (135.33±11.69) group developed marked tubula structural damage and higher paller scores (P<0.05) whereas significantly less tubular damage and lower paller scores were observed in EPO + I/R (135.33±11.69) group compared with I/R (250.67±23.96) group (P<0.05).
TUNEL assay: Compared with sham [(1.17±0.48)%] group, I/R [(24.58±4.39)%] and EPO+I/R [(8.52±2.06)%] group caused an increase in TUNEL-positive cells (P<0.05), compared with I/R [(24.58±4.39)%] group, EPO+I/R [(8.52±2.06)%] group TUNEL- positive cells were decressed (P<0.05).
Before ischemia: Up-regulation of Bcl-2 in the tubular epithelial cells was observed in EPO (135.00±9.89) and EPO + I/R (133.05±8.78) group compared with sham (55.17±7.76) group (P<0.05). Casepase-3 was no significant difference between Groups before ischemia.
After reperfusion: Diminished expression of Bcl-2 in I/R (28.12±6.49) group and up-regulation of Bcl-2 in EPO (133.08±8.92) and EPO + I/R (86.00±7.99) group were observed compared with sham (52.93±7.13) group (P<0.05), up-regulation of Casepase-3 in I/R (55.62±2.90) and EPO + I/R (45.77±2.08) group was observed compared with sham (18.53±1.86) group (P<0.05). Up-regulation of Bcl-2 and decreased expression of casepase-3 in EPO + I/R (Bcl-2, 86.00±7.99, Caspase-3, 45.77±2.08) group were observed compared with I/R (Bcl-2, 28.12±6.49, Caspase-3, 55.62±2.90) group (P<0.05).
Compared with before ischemia, Bcl-2 decreased and Casepase-3 incresed in I/R and EPO + I/R group after reperfusion (P<0.05), there was no significant difference between sham and EPO Group.
Conclusion
The results indicate that erythropoietin has protective effects on ischemic acute renal failure, the mechanisms seems to be associated with its amelioration of renal tubular epithelial cell apoptosis by up-regulation the anti-apoptosis protein Bcl-2 before ischemia which attenuated the diminished expression of Bcl-2 and decreased the up-regulation of protein Caspase-3 after ischemia/reperfusion.
引文
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