五肽化合物PLNPK对大鼠抗GBM肾炎的治疗作用及其作用机制的研究
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摘要
目的：
观察五肽化合物CMS010.26对大鼠抗肾小球基底膜(glomerular basement membrane, GBM)肾炎的治疗作用,并探讨其可能的作用机制。
方法：
1.提取大鼠GBM抗原,免疫家兔制备兔抗大鼠GBM抗血清,免疫球蛋白预免疫加尾静脉注射抗血清法建立大鼠抗GBM肾炎模型。
2.将抗GBM肾炎模型大鼠随机分为不同的处理组,包括PLNPK 200、400μg/kg/d剂量组和生理盐水组,另设正常对照组。观察PLNPK对肾炎模型大鼠24小时尿蛋白、血生化指标及肾指数的影响,同时应用HE病理染色、透射电镜和免疫荧光的方法,研究PLNPK对大鼠抗GBM肾炎是否具有治疗作用。
3.将给药一周后的各组大鼠的肾组织切片用CD68免疫组化染色的方法检测肾小球内聚集的巨噬细胞(macrophage, Mφ)的数量,观察PLNPK对大鼠抗GBM肾炎模型动物肾小球内Mφ聚集的影响。
4.提取各组大鼠的肾皮质内RNA和总蛋白,通过Real-Time PCR和Western Blot检测PLNPK对肾皮质内单核细胞趋化蛋白(monocyte chemoattractant protein, MCP-1)的表达水平的影响。
5.建立大鼠肾小球系膜细胞(mesangial, MC)体外培养体系,培养扩增大鼠系膜细胞系RMC。重组大鼠IL-1β刺激MC及RMC细胞,提取RNA和蛋白,通过Real-Time PCR和Western Blot检测PLNPK对MC及RMC中MCP-1表达的影响。
6.利用Western Blot检测PLNPK对MC及RMC细胞内p38促分裂原激活的蛋白激酶(mitogen-activated protein kinase, p38 MAPK)磷酸化的影响。
结果：
1.从注射抗血清的第二天,模型组大鼠24小时尿蛋白持续升高,和正常对照组相比P<0.01,抗血清注射两周后,肾小球内可见新月体形成,家兔异种抗体和大鼠自身抗体沿GBM呈线性沉积,表明该大鼠抗GBM肾炎模型成立。
2. PLNPK (200、400μg/kg/d)在给药2周后,能够降低肾炎模型大鼠24小时尿蛋白,6周后,能够升高血清总蛋白和白蛋白,降低血中尿素氮及胆固醇水平,但是对血清甘油三酯和肌酐水平的影响不明显。PLNPK可以降低肾指数,减少肾小球内新月体的形成数量。免疫荧光研究发现,200和400μg/kg/d的PLNPK可以明显减少肾小球基底膜自身抗体的沉积,透射电镜结果显示,PLNPK可以降低肾小球基底膜增厚和足细胞足突融合的程度。
3.大鼠抗GBM肾炎模型建立一周后,生理盐水组肾小球内可见大量Mφ聚集,正常对照组大鼠肾小球内未见Mφ。给予PLNPK (200、400μg/kg/d)治疗一周后,肾小球内Mφ聚集的数量明显减少,和生理盐水组相比P<0.01。
4.大鼠抗GBM肾炎模型建立一周后,生理盐水组肾皮质内MCP-1 mRNA转录水平和蛋白表达水平明显高于正常对照组,P<0.01。给予PLNPK (200. 400μg/kg/d)治疗一周后,肾皮质内MCP-1 mRNA转录水平和蛋白的表达水平明显降低,和生理盐水组相比P<0.01。
5.MC细胞和RMC细胞在受到大鼠IL-1β刺激作用5小时,MCP-1 mRNA转录水平明显升高,接受刺激12小时后,MCP-1蛋白水平已明显升高,PLNPK (1.6、3.2、6.4mg/ml)对于MC和RMC两种细胞MCP-1 mRNA转录和蛋白的表达均有明显的抑制作用,和IL-1β刺激组相比P<0.01。
6.MC细胞和RMC细胞在受到大鼠IL-1β刺激作用30minsp38 MAPK的磷酸化水平明显升高,用PLNPK (1.6、3.2、6.4mg/ml)预处理能够抑制MC和RMC两种细胞接受IL-1β刺激作用后p38 MAPK的磷酸化,和IL-1β刺激组相比P<0.01。
结论：PLNPK对大鼠抗GBM肾炎具有治疗作用,其可能的机制是：通过抑制大鼠肾小球系膜细胞p38 MAPK的磷酸化,从而抑制肾小球系膜细胞的活化,降低MCP-1的表达,进而减少肾小球内Mφ的聚集,减轻肾组织的损伤程度。
Objective:
To observe the therapeutic effect of pentapeptide compound PLNPK on anti-glomerular basement memberane (GBM) glomerularnephritis in rats, and investigate its possible therapeutic mechanism.
Methods:
1. The GBM antigen was extracted from the renal cortex of Wistar rats. The rabbits were immunized by rat GBM antigen to prepare the rabbit anti rat GBM serum. Glomerulonephritis was induced in male Wistar rats by preimmunization via an i.p. injection of rabbit IgG and followed by an intravenous injection of anti-GBM serum.
2. The rats with nephritis were divided into 3 treatment groups, which received i.p. injections of PLNPK (400μg/kg/d), PLNPK (200μg/kg/d) and normal saline (N.S.) respectively, another group of healthy rats served as a healthy control group. The therapeutic effect of PLNPK was evaluated by urinary protein detection, serumal biochemical indexes detection, renal index, renal histology, immunofluorescence, and ultrastructure examination by transmission electron microscopy.
3. The macrophages (Mφ) infiltrated into glomeruli were detected by CD68 immunohistological stain 7 days after the nephritis had been induced, and a quantitive analysis was performed to invest whether or not PLNPK could inhibite Mcp infiltration into glomeruli.
4. Total RNA and protein were extracted from renal cortex, monocyte chemoattractant protein (MCP)-1 mRNA and protein expression were detected by Real-Time PCR and Western Blot in order to observe whether PLNPK has any influence on MCP-1 expression in kidney.
5. Rat glomerular mesangial cells (MC) and rat glomerular mesangial cell strain, RMC, were cultured, and after stimulated by recombined rat IL-1β, Real-Time PCR and Western Blot were performed to detecte whether PLNPK could down regulate the expression of MCP-1 in above cells in vitro.
6. The effect of PLNPK on p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in MC and RMC was detected by Western Blot.
Results:
1. The 24hrs urinary protein of glomerular nephritis (GN) control group was much higher than that of healthy control from the second day after heterologous antibody had been injected (P<0.01), crescents could be observed in glomeruli, and heterologous antibody and auto-antibody deposited along GBM, which indicated that rat anti-GBM nephritis had been successfully induced.
2. After treated with PLNPK (200、400μg/kg/d) for 2 weeks, the urinary protein level of rats with nephritis was markedly reduced.6 weeks after the nephritis was induced, PLNPK could raise the level of serumal total protein (TP) and albumin (ALB), reduce serumal total cholesterol (TC) and serumal urea nitrogen (BUN), but the effect on serumal triglyceride (TG) and creatinine (Cr) was not significant. PLNPK could degrade the kidney index of the GN rats, reduce the formation of cerescents in glomeruli, lessened the deposition of auto-antibodies on the GBM. Ultrastructural analysis showed that PLNPK could ameliorate the injury of GBM, reduce the level of GBM thickening and foot processes fusion.
3. Considerable Mφinfiltrated into glomeruli one week after anti-GBM serum injection in GN control group, but no Mφwere seen in glomeruli of healthy rats. PLNPK (200 and 400μg/kg/d) could reduce the number of Mφin glomeruli (P<0.01 vs nephritis-induced group).
4. The expression of MCP-1 mRNA and protein was up regulated significantely in GN control group one week after nephritis was induced, P<0.01 vs healthy control. After treated with PLNPK (200、400μg/kg/d), both mRNA and protein expression of MCP-1 was reduced, P<0.01 vs GN control group.
5. The MCP-1 mRNA and protein expression was enhanced after stimulated by recombined rat IL-1βfor 5 and 12 hours respectively in MC and RMC, PLNPK (1.6,3.2,6.4mg/ml) reduced the IL-1βstimulated MCP-1 mRNA and protein expression in above cells, P<0.01 compared with IL-1βstimulated control.
6. The phosphorylation of p38 MAPK was inhanced after stimulated by rat IL-1βfor 30 minutes in MC and RMC, PLNPK (1.6、3.2、6.4mg/ml) pretreatment could reduce the phosphorylation level of p38 MAPK in those cells, P<0.01 vs IL-1βstimulated control.
Conclusion:
PLNPK can ameliorate rat anti-GBM glomerular nephritis, the possible mechanism (at least partly) is though inhibiting the phosphorylation of p38 MAPK, blocking the activation of MC, to reduce the expression of MCP-1 in MC, and decrease the Mφinfiltration into glomeruli, then reduced the injury of kidney.
观察五肽化合物CMS010.26对大鼠抗肾小球基底膜(glomerular basement membrane, GBM)肾炎的治疗作用,并探讨其可能的作用机制。
方法：
1.提取大鼠GBM抗原,免疫家兔制备兔抗大鼠GBM抗血清,免疫球蛋白预免疫加尾静脉注射抗血清法建立大鼠抗GBM肾炎模型。
2.将抗GBM肾炎模型大鼠随机分为不同的处理组,包括PLNPK 200、400μg/kg/d剂量组和生理盐水组,另设正常对照组。观察PLNPK对肾炎模型大鼠24小时尿蛋白、血生化指标及肾指数的影响,同时应用HE病理染色、透射电镜和免疫荧光的方法,研究PLNPK对大鼠抗GBM肾炎是否具有治疗作用。
3.将给药一周后的各组大鼠的肾组织切片用CD68免疫组化染色的方法检测肾小球内聚集的巨噬细胞(macrophage, Mφ)的数量,观察PLNPK对大鼠抗GBM肾炎模型动物肾小球内Mφ聚集的影响。
4.提取各组大鼠的肾皮质内RNA和总蛋白,通过Real-Time PCR和Western Blot检测PLNPK对肾皮质内单核细胞趋化蛋白(monocyte chemoattractant protein, MCP-1)的表达水平的影响。
5.建立大鼠肾小球系膜细胞(mesangial, MC)体外培养体系,培养扩增大鼠系膜细胞系RMC。重组大鼠IL-1β刺激MC及RMC细胞,提取RNA和蛋白,通过Real-Time PCR和Western Blot检测PLNPK对MC及RMC中MCP-1表达的影响。
6.利用Western Blot检测PLNPK对MC及RMC细胞内p38促分裂原激活的蛋白激酶(mitogen-activated protein kinase, p38 MAPK)磷酸化的影响。
结果：
1.从注射抗血清的第二天,模型组大鼠24小时尿蛋白持续升高,和正常对照组相比P<0.01,抗血清注射两周后,肾小球内可见新月体形成,家兔异种抗体和大鼠自身抗体沿GBM呈线性沉积,表明该大鼠抗GBM肾炎模型成立。
2. PLNPK (200、400μg/kg/d)在给药2周后,能够降低肾炎模型大鼠24小时尿蛋白,6周后,能够升高血清总蛋白和白蛋白,降低血中尿素氮及胆固醇水平,但是对血清甘油三酯和肌酐水平的影响不明显。PLNPK可以降低肾指数,减少肾小球内新月体的形成数量。免疫荧光研究发现,200和400μg/kg/d的PLNPK可以明显减少肾小球基底膜自身抗体的沉积,透射电镜结果显示,PLNPK可以降低肾小球基底膜增厚和足细胞足突融合的程度。
3.大鼠抗GBM肾炎模型建立一周后,生理盐水组肾小球内可见大量Mφ聚集,正常对照组大鼠肾小球内未见Mφ。给予PLNPK (200、400μg/kg/d)治疗一周后,肾小球内Mφ聚集的数量明显减少,和生理盐水组相比P<0.01。
4.大鼠抗GBM肾炎模型建立一周后,生理盐水组肾皮质内MCP-1 mRNA转录水平和蛋白表达水平明显高于正常对照组,P<0.01。给予PLNPK (200. 400μg/kg/d)治疗一周后,肾皮质内MCP-1 mRNA转录水平和蛋白的表达水平明显降低,和生理盐水组相比P<0.01。
5.MC细胞和RMC细胞在受到大鼠IL-1β刺激作用5小时,MCP-1 mRNA转录水平明显升高,接受刺激12小时后,MCP-1蛋白水平已明显升高,PLNPK (1.6、3.2、6.4mg/ml)对于MC和RMC两种细胞MCP-1 mRNA转录和蛋白的表达均有明显的抑制作用,和IL-1β刺激组相比P<0.01。
6.MC细胞和RMC细胞在受到大鼠IL-1β刺激作用30minsp38 MAPK的磷酸化水平明显升高,用PLNPK (1.6、3.2、6.4mg/ml)预处理能够抑制MC和RMC两种细胞接受IL-1β刺激作用后p38 MAPK的磷酸化,和IL-1β刺激组相比P<0.01。
结论：PLNPK对大鼠抗GBM肾炎具有治疗作用,其可能的机制是：通过抑制大鼠肾小球系膜细胞p38 MAPK的磷酸化,从而抑制肾小球系膜细胞的活化,降低MCP-1的表达,进而减少肾小球内Mφ的聚集,减轻肾组织的损伤程度。
Objective:
To observe the therapeutic effect of pentapeptide compound PLNPK on anti-glomerular basement memberane (GBM) glomerularnephritis in rats, and investigate its possible therapeutic mechanism.
Methods:
1. The GBM antigen was extracted from the renal cortex of Wistar rats. The rabbits were immunized by rat GBM antigen to prepare the rabbit anti rat GBM serum. Glomerulonephritis was induced in male Wistar rats by preimmunization via an i.p. injection of rabbit IgG and followed by an intravenous injection of anti-GBM serum.
2. The rats with nephritis were divided into 3 treatment groups, which received i.p. injections of PLNPK (400μg/kg/d), PLNPK (200μg/kg/d) and normal saline (N.S.) respectively, another group of healthy rats served as a healthy control group. The therapeutic effect of PLNPK was evaluated by urinary protein detection, serumal biochemical indexes detection, renal index, renal histology, immunofluorescence, and ultrastructure examination by transmission electron microscopy.
3. The macrophages (Mφ) infiltrated into glomeruli were detected by CD68 immunohistological stain 7 days after the nephritis had been induced, and a quantitive analysis was performed to invest whether or not PLNPK could inhibite Mcp infiltration into glomeruli.
4. Total RNA and protein were extracted from renal cortex, monocyte chemoattractant protein (MCP)-1 mRNA and protein expression were detected by Real-Time PCR and Western Blot in order to observe whether PLNPK has any influence on MCP-1 expression in kidney.
5. Rat glomerular mesangial cells (MC) and rat glomerular mesangial cell strain, RMC, were cultured, and after stimulated by recombined rat IL-1β, Real-Time PCR and Western Blot were performed to detecte whether PLNPK could down regulate the expression of MCP-1 in above cells in vitro.
6. The effect of PLNPK on p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation in MC and RMC was detected by Western Blot.
Results:
1. The 24hrs urinary protein of glomerular nephritis (GN) control group was much higher than that of healthy control from the second day after heterologous antibody had been injected (P<0.01), crescents could be observed in glomeruli, and heterologous antibody and auto-antibody deposited along GBM, which indicated that rat anti-GBM nephritis had been successfully induced.
2. After treated with PLNPK (200、400μg/kg/d) for 2 weeks, the urinary protein level of rats with nephritis was markedly reduced.6 weeks after the nephritis was induced, PLNPK could raise the level of serumal total protein (TP) and albumin (ALB), reduce serumal total cholesterol (TC) and serumal urea nitrogen (BUN), but the effect on serumal triglyceride (TG) and creatinine (Cr) was not significant. PLNPK could degrade the kidney index of the GN rats, reduce the formation of cerescents in glomeruli, lessened the deposition of auto-antibodies on the GBM. Ultrastructural analysis showed that PLNPK could ameliorate the injury of GBM, reduce the level of GBM thickening and foot processes fusion.
3. Considerable Mφinfiltrated into glomeruli one week after anti-GBM serum injection in GN control group, but no Mφwere seen in glomeruli of healthy rats. PLNPK (200 and 400μg/kg/d) could reduce the number of Mφin glomeruli (P<0.01 vs nephritis-induced group).
4. The expression of MCP-1 mRNA and protein was up regulated significantely in GN control group one week after nephritis was induced, P<0.01 vs healthy control. After treated with PLNPK (200、400μg/kg/d), both mRNA and protein expression of MCP-1 was reduced, P<0.01 vs GN control group.
5. The MCP-1 mRNA and protein expression was enhanced after stimulated by recombined rat IL-1βfor 5 and 12 hours respectively in MC and RMC, PLNPK (1.6,3.2,6.4mg/ml) reduced the IL-1βstimulated MCP-1 mRNA and protein expression in above cells, P<0.01 compared with IL-1βstimulated control.
6. The phosphorylation of p38 MAPK was inhanced after stimulated by rat IL-1βfor 30 minutes in MC and RMC, PLNPK (1.6、3.2、6.4mg/ml) pretreatment could reduce the phosphorylation level of p38 MAPK in those cells, P<0.01 vs IL-1βstimulated control.
Conclusion:
PLNPK can ameliorate rat anti-GBM glomerular nephritis, the possible mechanism (at least partly) is though inhibiting the phosphorylation of p38 MAPK, blocking the activation of MC, to reduce the expression of MCP-1 in MC, and decrease the Mφinfiltration into glomeruli, then reduced the injury of kidney.
引文
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