FTY720对5/6肾切除大鼠肾小球硬化及细胞周期调节蛋白表达的影响
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摘要
目的观察新型免疫抑制剂FTY720对5/6肾切除大鼠肾小球硬化的影响,细胞外基质(extracellular matrix, ECM)成分表达的和细胞周期调节蛋白(Cell Cycle Regulatory Protein, CCRP)表达的影响。并探讨FTY720对肾小球硬化的作用机制。
方法选用SD雄性大鼠24只,分为假手术组、模型组和FTY720治疗组,每组8只。模型组及治疗组采用5/6肾切除制作肾小球硬化的模型,末次手术后治疗组给予FTY720[0.5mg/kg·d]灌胃。分别于术前和术后2w、4w、8w、12w检测大鼠24小时尿蛋白定量;术前及术后8w、12w检测血尿素氮及肌酐;术后12周处死并对大鼠肾脏做病理组织学分析;采用免疫组化方法检测Ⅳ型胶原(Col-Ⅳ)、纤维连接蛋白(FN)的表达水平及细胞周期调控蛋白细胞周期素E(cyclinE)、p21、p27和增殖细胞核抗原(PNCA)的表达。
结果假手术组24h尿蛋白量在术前和术后2w、4w、8w、12w分别为(2.92±0.68 )mg·d-1﹑(3.72±0.61) mg·d-1﹑(4.05±1.08 )mg·d-1﹑(4.29±0.77 )mg·d-1﹑(5.15±0.82 )mg·d-1。与假手术组相比,模型组24h尿蛋白量在术后2w开始升高,为(8.07±1.61 )mg·d-1,以后逐渐增高,12w达(28.6±12.21 )mg·d-1,治疗组24h尿蛋白量在术后4w开始较模型组显著减低,为(9.9±1.49) mg·d-1,12w时为(11.35±2.09) mg·d-1,减低更明显(P﹤0.01)。假手术组术前和术后8w、12w血肌酐分别为(27.85±8.23)μmol·L-1﹑(28.33±5.0)μmol·L-1﹑(29.2±4.23)μmol·L-1,模型组术后8w血肌酐升高达(61.08±4.28)μmol·L-1,12w时为(130.2±23.9)μmol·L-1,升高更明显(P﹤0.05);治疗组血肌酐则未见明显升高,12w时为(80.19±7.11)μmol·L-1,较模型组显著减低(P﹤0.05);各组血尿素氮与肌酐变化相似。肾脏病理和免疫组化染色显示,FTY720能明显减轻大鼠硬化程度,抑制肾小球内细胞外基质Col-Ⅳ、FN的表达。细胞周期调控蛋白研究结果表明FTY720能升高肾小球p27表达,降低p21﹑cyclinE表达,下调PCNA的表达,p21、cyclinE和PCNA明显低于模型组,但仍稍高于假手术组,p27明显高于模型组,与正常组无明显区别。
结论FTY720能显著降低5/6肾切除大鼠的24小时尿蛋白量,防止肾小球硬化,其作用与降低肾小球细胞cyclinE表达,增加p27表达并下调PCNA的表达,减轻肾小球细胞增殖和减少Col-Ⅳ、FN聚积有关。
Object To study the effect of FTY720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats.
Methods 24 rats were divided into sham-operation group, glomerulosclerosis model group and FTY720 treated glomerulosclerosis group, 8 rats in each groups. The rats in later two groups were subjected to 5/6 nephrectomy. After operation, rat in the treat group was fed with FTY720 at 0.5/mg﹒d for 12 weeks. Urine protein excretion was measured before opertion and 2w, 4w, 8w, 12w. Then, the rats were sacrificed and the left kidneys were subjected to pathological evaluation. The expression of collagenⅣ, fibronectin, and cyclinE, p21, p27 , PCNA were determined by immunohistochemistry methods.
Results The daily urine protein (Up) in sham-operation group was (2.92±0.68 ) mg·d-1 before operation, and (3.72±0.61) mg·d-1 at 2w, (4.05±1.08) mg·d-1 at 8w, 4.29±0.77 )mg·d-1 at 12w. The model group showed higher daily urine protein excretion from 2w, (8.07±1.61) mg·d-1 and thereafter. At 12w, the Up increased to (28.6±12.21) mg·d-1 in model group, significantly higher than in sham-operation group (P<0.05). After treatment with FTY720, Up began to decrease from 4w after operation,(9.9±1.49)mg·d-1 at that time and(11.35±2.09)mg·d-1 at 12w, both were significantly lower than in model group (p<0.01). Scr level in sham-operation group was (27.85±8.23)μmol·L-1 before operation and(28.33±5.0)μmol·L-1 at 8w, (29.2±4.23)μmol·L-1 at 12w. The model group showed higher level of Scr from 8w, (61.08±4.28)μmol·L-1 at that time, (130.2±23.9)μmol·L-1at 12w, both were much higher than in sham-operation group (P<0.05). In FTY720 treated group, Scr level were (80.19±7.11)μmol·L-1 at 12w, much lower than in model group. The time course changes of BUN were similar to Scr in each group. Renal pathology and immunohistological evaluation showed that FTY720 could obviously inhibit the expressionof col-Ⅳand FN in glomeruli and attenuate the extent of glomerulosclerosis. Moreover, FTY720 could upregulate glomerular expression of p27 and downregulate glomerular expression of p21 and cyclinE. The expression of p21, cyclinE and PCNA were significantly lower in treatment group than in model group (P<0.05), but still higher than in sham-operation group (P<0.05). p27 expression in glomeruli was higher in treatment group than that in model group (P<0.05), and lower than that in normal group but without significant statistic difference.
Conclusion FTY720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotal nephrectomized rats. This protective effect is presumed to be associated with its role in downregulation of cyclinE expression and upregulation of p27 expression in glomerular cells, and inhibition of extracellular matrix accumulation in glomeruli.
方法选用SD雄性大鼠24只,分为假手术组、模型组和FTY720治疗组,每组8只。模型组及治疗组采用5/6肾切除制作肾小球硬化的模型,末次手术后治疗组给予FTY720[0.5mg/kg·d]灌胃。分别于术前和术后2w、4w、8w、12w检测大鼠24小时尿蛋白定量;术前及术后8w、12w检测血尿素氮及肌酐;术后12周处死并对大鼠肾脏做病理组织学分析;采用免疫组化方法检测Ⅳ型胶原(Col-Ⅳ)、纤维连接蛋白(FN)的表达水平及细胞周期调控蛋白细胞周期素E(cyclinE)、p21、p27和增殖细胞核抗原(PNCA)的表达。
结果假手术组24h尿蛋白量在术前和术后2w、4w、8w、12w分别为(2.92±0.68 )mg·d-1﹑(3.72±0.61) mg·d-1﹑(4.05±1.08 )mg·d-1﹑(4.29±0.77 )mg·d-1﹑(5.15±0.82 )mg·d-1。与假手术组相比,模型组24h尿蛋白量在术后2w开始升高,为(8.07±1.61 )mg·d-1,以后逐渐增高,12w达(28.6±12.21 )mg·d-1,治疗组24h尿蛋白量在术后4w开始较模型组显著减低,为(9.9±1.49) mg·d-1,12w时为(11.35±2.09) mg·d-1,减低更明显(P﹤0.01)。假手术组术前和术后8w、12w血肌酐分别为(27.85±8.23)μmol·L-1﹑(28.33±5.0)μmol·L-1﹑(29.2±4.23)μmol·L-1,模型组术后8w血肌酐升高达(61.08±4.28)μmol·L-1,12w时为(130.2±23.9)μmol·L-1,升高更明显(P﹤0.05);治疗组血肌酐则未见明显升高,12w时为(80.19±7.11)μmol·L-1,较模型组显著减低(P﹤0.05);各组血尿素氮与肌酐变化相似。肾脏病理和免疫组化染色显示,FTY720能明显减轻大鼠硬化程度,抑制肾小球内细胞外基质Col-Ⅳ、FN的表达。细胞周期调控蛋白研究结果表明FTY720能升高肾小球p27表达,降低p21﹑cyclinE表达,下调PCNA的表达,p21、cyclinE和PCNA明显低于模型组,但仍稍高于假手术组,p27明显高于模型组,与正常组无明显区别。
结论FTY720能显著降低5/6肾切除大鼠的24小时尿蛋白量,防止肾小球硬化,其作用与降低肾小球细胞cyclinE表达,增加p27表达并下调PCNA的表达,减轻肾小球细胞增殖和减少Col-Ⅳ、FN聚积有关。
Object To study the effect of FTY720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats.
Methods 24 rats were divided into sham-operation group, glomerulosclerosis model group and FTY720 treated glomerulosclerosis group, 8 rats in each groups. The rats in later two groups were subjected to 5/6 nephrectomy. After operation, rat in the treat group was fed with FTY720 at 0.5/mg﹒d for 12 weeks. Urine protein excretion was measured before opertion and 2w, 4w, 8w, 12w. Then, the rats were sacrificed and the left kidneys were subjected to pathological evaluation. The expression of collagenⅣ, fibronectin, and cyclinE, p21, p27 , PCNA were determined by immunohistochemistry methods.
Results The daily urine protein (Up) in sham-operation group was (2.92±0.68 ) mg·d-1 before operation, and (3.72±0.61) mg·d-1 at 2w, (4.05±1.08) mg·d-1 at 8w, 4.29±0.77 )mg·d-1 at 12w. The model group showed higher daily urine protein excretion from 2w, (8.07±1.61) mg·d-1 and thereafter. At 12w, the Up increased to (28.6±12.21) mg·d-1 in model group, significantly higher than in sham-operation group (P<0.05). After treatment with FTY720, Up began to decrease from 4w after operation,(9.9±1.49)mg·d-1 at that time and(11.35±2.09)mg·d-1 at 12w, both were significantly lower than in model group (p<0.01). Scr level in sham-operation group was (27.85±8.23)μmol·L-1 before operation and(28.33±5.0)μmol·L-1 at 8w, (29.2±4.23)μmol·L-1 at 12w. The model group showed higher level of Scr from 8w, (61.08±4.28)μmol·L-1 at that time, (130.2±23.9)μmol·L-1at 12w, both were much higher than in sham-operation group (P<0.05). In FTY720 treated group, Scr level were (80.19±7.11)μmol·L-1 at 12w, much lower than in model group. The time course changes of BUN were similar to Scr in each group. Renal pathology and immunohistological evaluation showed that FTY720 could obviously inhibit the expressionof col-Ⅳand FN in glomeruli and attenuate the extent of glomerulosclerosis. Moreover, FTY720 could upregulate glomerular expression of p27 and downregulate glomerular expression of p21 and cyclinE. The expression of p21, cyclinE and PCNA were significantly lower in treatment group than in model group (P<0.05), but still higher than in sham-operation group (P<0.05). p27 expression in glomeruli was higher in treatment group than that in model group (P<0.05), and lower than that in normal group but without significant statistic difference.
Conclusion FTY720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotal nephrectomized rats. This protective effect is presumed to be associated with its role in downregulation of cyclinE expression and upregulation of p27 expression in glomerular cells, and inhibition of extracellular matrix accumulation in glomeruli.
引文
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