五肽化合物PLNPK对被动型Heymann肾炎的治疗作用及机理研究
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摘要
目的:
建立大鼠被动型Heymann肾炎(PHN)模型,研究五肽化合物PLNPK对大鼠PHN的治疗作用,初步探讨其作用机制。
方法:
1.制备大鼠FX1A抗原,兔皮内免疫制备兔抗大鼠FX1A的抗血清,免疫双向扩散法检测抗血清效价;大鼠尾静脉注射不同剂量的抗血清,并设立正常对照。每两周检测各组大鼠24hrs尿蛋白、血清肌酐(CR)、尿素氮(BUN)、总甘油三脂(TC)、总胆固醇(TG)、白蛋白(ALB)等指标,观察各组肾脏病理学的改变,确定建立PHN模型所用抗FX1A抗血清的最适剂量。
2.大鼠尾静脉注射兔抗大鼠FX1A抗血清,建立大鼠被动型Heymann肾炎模型。尾静脉注射次日腹腔注射PLNPK,持续10周。每两周检测各组大鼠24hrs尿蛋白、血清CR、BUN、TC、TG、ALB,观察PLNPK对PHN大鼠尿蛋白及肾脏功能的影响;观察PLNPK对PHN大鼠肾指数的影响;肾脏HE染色观察PLNPK对PHN大鼠病理学的影响;肾脏PASM染色观察PLNPK对PHN大鼠肾脏基底膜成分的影响。
3.透射电镜检测PLNPK对PHN大鼠足细胞损伤的影响;RT-PCR和WesternBlot检测PLNPK对PHN大鼠足细胞nephrin和podocin mRNA和蛋白表达的影响;ELISA检测PLNPK对PHN大鼠C5b-9生成的影响;间接免疫荧光法检测PLNPK对PHN大鼠肾脏IgG沉积的影响。
结果:
1.免疫双向扩散结果显示兔抗大鼠FX1A抗血清效价达到1:32。3ml抗血清注射组大鼠24hrs尿蛋白及BUN、CR、TC、TG升高,ALB降低,与正常对照组比较,有统计学意义(P＜0.05)。3ml抗血清注射组大鼠肾脏病理损伤明显,出现基底膜弥漫性增厚;1.6ml、2ml抗血清注射组大鼠24h尿蛋白及血清BUN、CR、TC、TG、ALB变化幅度较小,且有恢复趋势,病理改变不明显;3.6ml抗血清注射组大鼠死亡率较高,病理偶有蛋白管型出现。确定3ml抗血清为建立PHN模型的最适剂量。
2.PLNPK(100、200、400μg/kg/d)可以显著降低PHN大鼠的24hrs尿蛋白水平(P＜0.05);PLNPK(100、200、400μg/kg/d)可以显著降低PHN大鼠血清TC、TG、BUN、CR水平(P＜0.05),并显著升高PHN大鼠血清ALB水平(P＜0.05);病理结果表明:PLNPK可以改善PHN大鼠肾脏的病理损伤,减少毛细血管壁增厚和上皮细胞肿胀现象。
3.PLNPK(100、200、400μg/kg/d)可以改善PHN大鼠足细胞损伤;可以明显升高PHN大鼠nephrin和podocin的蛋白表达(P＜0.05);ELISA结果表明,PLNPK(100、200、400μg/kg/d)可以明显减少PHN大鼠尿中C5b-9含量(P＜0.05);并减少PHN大鼠肾脏IgG沉积现象。
结论:
PLNPK可以通过减少PHN大鼠肾脏IgG的沉积,进一步减少C5b-9的生成,减轻肾组织免疫损伤,增高足细胞上裂孔蛋白nephrin和podocin的表达,改善足细胞的损伤,从而达到能有效地减少大量蛋白尿及治疗大鼠PHN的作用。
Objective:
To set up animal model of rat passive Heymann nephritis(PHN),and to investigate the therapeutic effect of pentapeptide compound PLNPK on PHN and its possible mechanisms.
Methods:
1.Prepared the antigen of rat-FX1A,and immuned rabbit intraderrnally to get anti-FX1A serum,detected serum titer by two-way immune diffusion method; PHN model was induced in SD rats by an intravenous injection of anti-FX1A serum respectively,and establish normal control.24hrs urinine protein,serum creatinine,urea nitrogen,triglyceride(TG),total cholesterol(TC),albumin(ALB) was detected every two weeks,and observed pathological changes of each group, decided the optimum of anti-FX1A serum.
2.PHN model was induced in SD rats by an intravenous injection of anti-FX1A serum,PLNPK were injected.ip from the 1st day to the end of the experiment. 24hrs urine protein,serum creatinine,urea nitrogen,triglyceride(TG),total cholesterol(TC),albumin(ALB)was detected every two weeks to observe the effect of PLNPK on rats urine protein and renal function with PHN;Observed the effect of PLNPK on rats renal index with PHN;Observed the effect of PLNPK on pathological changes of rats kidney by HE staining and the basement membrane components by PASM staining.
3.Detected the effect of PLNPK on podocyte damage of PHN rats by transmission electron microscopy;Detected the effect of PLNPK on mRNA & protein of nephrin and podocin by RT-PCR and Western Blot;Detected the effect of PLNPK on C5b-9 of PHN rats by ELISA;Detected the effect of PLNPK on IgG sedimentation of PHN rats kidney by indirect immunofluorescence.
Results:
1.After 5 immunizations,immune diffusion showed that the serum titer was 1:32. 24hrs urine protein,BUN,CR,TC,TG of 3ml serum group were stepped up and ALB was stepped down vs normal control group(P＜0.05).The renal damage of 3ml group showed thickened basal membrane widespreadly;The change extent of 24hrs urine protein,BUN,CR,TC,TG of 1.6ml and 2ml were small vs normal control group,and pathological changes were unobviously;The death rate of 3.6ml group was high, protein cast appeared occasionally.3ml serum was the optimum dose of PHN model establishment.
2.PLNPK(100,200,400μg/kg/d)could degrade the level of 24hrs urine protein (P＜0.05),could degrade the level of serum TC,TG,BUN,CR(P＜0.05);pathological result indicated that PLNPK could ameliorate the renal change of PHN rat,and impaire the phenomenon of thickened capillary wall and podocyte swelling.
3.PLNPK(100、200、400μg/kg/d)can ameliorate the podocyte damage;it can up-regulate protein expressions of nephrin and podocin with PHN rats(P＜0.05);it can decrease the content of C5b-9 of PHN rats urine(P＜0.05);and it can decrease the IgG sedimentation of PHN rats kidney.
Conclusions:
PLNPK can decrease the IgG sedimentation of PHN rats kidney,ameliorate renal immunization-pathology damage,up-regulate the expression of nephrin and podocin on podocyte,and ameliorate the damage of podocyte,can decrease the urine protein effectively and to cure the PHN.
建立大鼠被动型Heymann肾炎(PHN)模型,研究五肽化合物PLNPK对大鼠PHN的治疗作用,初步探讨其作用机制。
方法:
1.制备大鼠FX1A抗原,兔皮内免疫制备兔抗大鼠FX1A的抗血清,免疫双向扩散法检测抗血清效价;大鼠尾静脉注射不同剂量的抗血清,并设立正常对照。每两周检测各组大鼠24hrs尿蛋白、血清肌酐(CR)、尿素氮(BUN)、总甘油三脂(TC)、总胆固醇(TG)、白蛋白(ALB)等指标,观察各组肾脏病理学的改变,确定建立PHN模型所用抗FX1A抗血清的最适剂量。
2.大鼠尾静脉注射兔抗大鼠FX1A抗血清,建立大鼠被动型Heymann肾炎模型。尾静脉注射次日腹腔注射PLNPK,持续10周。每两周检测各组大鼠24hrs尿蛋白、血清CR、BUN、TC、TG、ALB,观察PLNPK对PHN大鼠尿蛋白及肾脏功能的影响;观察PLNPK对PHN大鼠肾指数的影响;肾脏HE染色观察PLNPK对PHN大鼠病理学的影响;肾脏PASM染色观察PLNPK对PHN大鼠肾脏基底膜成分的影响。
3.透射电镜检测PLNPK对PHN大鼠足细胞损伤的影响;RT-PCR和WesternBlot检测PLNPK对PHN大鼠足细胞nephrin和podocin mRNA和蛋白表达的影响;ELISA检测PLNPK对PHN大鼠C5b-9生成的影响;间接免疫荧光法检测PLNPK对PHN大鼠肾脏IgG沉积的影响。
结果:
1.免疫双向扩散结果显示兔抗大鼠FX1A抗血清效价达到1:32。3ml抗血清注射组大鼠24hrs尿蛋白及BUN、CR、TC、TG升高,ALB降低,与正常对照组比较,有统计学意义(P＜0.05)。3ml抗血清注射组大鼠肾脏病理损伤明显,出现基底膜弥漫性增厚;1.6ml、2ml抗血清注射组大鼠24h尿蛋白及血清BUN、CR、TC、TG、ALB变化幅度较小,且有恢复趋势,病理改变不明显;3.6ml抗血清注射组大鼠死亡率较高,病理偶有蛋白管型出现。确定3ml抗血清为建立PHN模型的最适剂量。
2.PLNPK(100、200、400μg/kg/d)可以显著降低PHN大鼠的24hrs尿蛋白水平(P＜0.05);PLNPK(100、200、400μg/kg/d)可以显著降低PHN大鼠血清TC、TG、BUN、CR水平(P＜0.05),并显著升高PHN大鼠血清ALB水平(P＜0.05);病理结果表明:PLNPK可以改善PHN大鼠肾脏的病理损伤,减少毛细血管壁增厚和上皮细胞肿胀现象。
3.PLNPK(100、200、400μg/kg/d)可以改善PHN大鼠足细胞损伤;可以明显升高PHN大鼠nephrin和podocin的蛋白表达(P＜0.05);ELISA结果表明,PLNPK(100、200、400μg/kg/d)可以明显减少PHN大鼠尿中C5b-9含量(P＜0.05);并减少PHN大鼠肾脏IgG沉积现象。
结论:
PLNPK可以通过减少PHN大鼠肾脏IgG的沉积,进一步减少C5b-9的生成,减轻肾组织免疫损伤,增高足细胞上裂孔蛋白nephrin和podocin的表达,改善足细胞的损伤,从而达到能有效地减少大量蛋白尿及治疗大鼠PHN的作用。
Objective:
To set up animal model of rat passive Heymann nephritis(PHN),and to investigate the therapeutic effect of pentapeptide compound PLNPK on PHN and its possible mechanisms.
Methods:
1.Prepared the antigen of rat-FX1A,and immuned rabbit intraderrnally to get anti-FX1A serum,detected serum titer by two-way immune diffusion method; PHN model was induced in SD rats by an intravenous injection of anti-FX1A serum respectively,and establish normal control.24hrs urinine protein,serum creatinine,urea nitrogen,triglyceride(TG),total cholesterol(TC),albumin(ALB) was detected every two weeks,and observed pathological changes of each group, decided the optimum of anti-FX1A serum.
2.PHN model was induced in SD rats by an intravenous injection of anti-FX1A serum,PLNPK were injected.ip from the 1st day to the end of the experiment. 24hrs urine protein,serum creatinine,urea nitrogen,triglyceride(TG),total cholesterol(TC),albumin(ALB)was detected every two weeks to observe the effect of PLNPK on rats urine protein and renal function with PHN;Observed the effect of PLNPK on rats renal index with PHN;Observed the effect of PLNPK on pathological changes of rats kidney by HE staining and the basement membrane components by PASM staining.
3.Detected the effect of PLNPK on podocyte damage of PHN rats by transmission electron microscopy;Detected the effect of PLNPK on mRNA & protein of nephrin and podocin by RT-PCR and Western Blot;Detected the effect of PLNPK on C5b-9 of PHN rats by ELISA;Detected the effect of PLNPK on IgG sedimentation of PHN rats kidney by indirect immunofluorescence.
Results:
1.After 5 immunizations,immune diffusion showed that the serum titer was 1:32. 24hrs urine protein,BUN,CR,TC,TG of 3ml serum group were stepped up and ALB was stepped down vs normal control group(P＜0.05).The renal damage of 3ml group showed thickened basal membrane widespreadly;The change extent of 24hrs urine protein,BUN,CR,TC,TG of 1.6ml and 2ml were small vs normal control group,and pathological changes were unobviously;The death rate of 3.6ml group was high, protein cast appeared occasionally.3ml serum was the optimum dose of PHN model establishment.
2.PLNPK(100,200,400μg/kg/d)could degrade the level of 24hrs urine protein (P＜0.05),could degrade the level of serum TC,TG,BUN,CR(P＜0.05);pathological result indicated that PLNPK could ameliorate the renal change of PHN rat,and impaire the phenomenon of thickened capillary wall and podocyte swelling.
3.PLNPK(100、200、400μg/kg/d)can ameliorate the podocyte damage;it can up-regulate protein expressions of nephrin and podocin with PHN rats(P＜0.05);it can decrease the content of C5b-9 of PHN rats urine(P＜0.05);and it can decrease the IgG sedimentation of PHN rats kidney.
Conclusions:
PLNPK can decrease the IgG sedimentation of PHN rats kidney,ameliorate renal immunization-pathology damage,up-regulate the expression of nephrin and podocin on podocyte,and ameliorate the damage of podocyte,can decrease the urine protein effectively and to cure the PHN.
引文
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