SublyticC5b-9诱导IRF-1表达对Thy-1肾炎大鼠GMCs凋亡病变的影响
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摘要
第一部分体外研究IRF-1在sublytic C5b-9诱导大鼠GMCs凋亡病变中的作用
目的:体外探讨亚溶解型C5b-9(sublytic C5b-9)刺激大鼠肾小球系膜细胞(glomerular mesangial cells,GMCs)上调干扰素调节因子1(interferon regulatory factor 1, IRF-1)基因表达、并发凋亡现象以及半胱氨酸天冬氨酸特异性蛋白酶(Caspase)的活化情况,同时确定过表达或沉默IRF-1基因对sublytic C5b-9诱发大鼠GMCs凋亡病变的影响以及沉默IRF-1基因对cleaved Caspase 9、cleaved Caspase 8和cleaved Caspase 3蛋白表达的影响,同时,检查使用Caspase抑制剂对sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡现象的影响。方法:先体外培养大鼠GMCs并给予sublytic C5b-9刺激(实验设不同处理对照),用RT-PCR和Western blot分别检查受sublytic C5b-9刺激的GMCs上调IRF-1 mRNA的丰度及蛋白表达的水平,并用流式细胞术(Flow Cytometry, FCM)分析各组GMCs的凋亡情况,同时用Western blot检查sublytic C5b-9刺激的GMCs中Caspase的活化情况。然后,分别将构建的IRF-1过表达质粒和发夹式小干涉RNA(short hairpin RNA, shRNA)质粒转染GMCs,并将GMCs作相应的分组处理,定量分析各组GMCs的凋亡率,同时检查转染IRF-1 shRNA质粒的GMCs和对照组GMCs中cleaved Caspase 9、cleaved Caspase 8和cleaved Caspase 3蛋白的表达情况。此外,使用Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)处理大鼠GMCs,观察其对sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡病变的影响。结果:Sublytic C5b-9刺激大鼠GMCs早期可见IRF-1表达上调并伴随GMCs的凋亡以及Caspase的活化,过表达IRF-1可促进sublytic C5b-9刺激引起的GMCs凋亡病变,而用IRF-1 shRNA不仅可以使sublytic C5b-9刺激的GMCs的凋亡率下降,也可以减少sublytic C5b-9刺激的GMCs中上调cleaved Caspase 8和cleaved Caspase 3的表达量,但对cleaved Caspase 9表达的影响并不显著。此外,应用Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)亦可显著减轻由sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡数量。结论:Sublytic C5b-9诱导的大鼠GMCs凋亡病变可能与其上调IRF-1表达及激活Caspase有一定的关系。
第二部分体内探讨沉默IRF-1基因对Thy-1N大鼠GMCs凋亡以及继发增生病变的抑制效应
目的:探讨用IRF-1 shRNA沉默大鼠肾组织内IRF-1基因对Thy-1肾炎(Thy-1 nephritis, Thy-1N)大鼠GMCs凋亡和继发增生病变的抑制作用。方法:首先,复制大鼠Thy-1N模型,定期采用RT-PCR和Western blot方法检查其肾组织中IRF-1和cleaved Caspase 9、8和3蛋白的表达情况。然后应用肾动脉灌注加电导入方法,将IRF-1 shRNA质粒导入大鼠肾组织,再经尾静脉注射注射抗胸腺细胞血清(anti-thymocyte serum,ATS)复制大鼠Thy-1N模型。同时尾静脉注射Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)后再复制大鼠Thy-1N模型。分别取注射ATS后3h和7d时的大鼠肾组织,应用Western blot检查3h时肾组织中IRF-1蛋白的表达水平及cleaved Caspase 9、8和3蛋白的表达情况。此外,应用末端转移酶介导的dUTP缺口末端标记(terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL)技术和电镜检查3h时肾组织的病理学改变。另光镜检查计数7d时肾小球内的细胞总数,并用生化方法测定各组大鼠24h和7d时尿蛋白总量的变化。结果:大鼠Thy-1N病变3h时,肾组织中IRF-1的表达水平明显升高。IRF-1 shRNA处理的Thy-1N大鼠(IRF-1 shRNA+Thy-1N组),其肾组织中IRF-1基因的表达以及Caspase 8和Caspase 3的活化水平显著低于Thy-1N模型组。另IRF-1 shRNA+Thy-1N组大鼠以及经Caspase抑制剂处理的大鼠(Z-IETD-FMK+Thy-1N组和Z-DEVD-FMK+Thy-1N组),3h时肾小球内GMCs凋亡数量显著减少。实验7d时,肾小球细胞的增生程度有所减轻,并且,24h尿蛋白的分泌量也明显减少。结论:沉默大鼠肾组织内IRF-1基因以及使用Caspase抑制剂均能明显减轻Thy-1N大鼠GMCs的凋亡病变及继发增生现象,包括尿蛋白的分泌。
第三部分体外研究sublytic C5b-9刺激大鼠GMCs启动IRF-1转录的作用及其信号通路
目的:研究sublytic C5b-9刺激大鼠GMCs启动IRF-1转录的作用,同时,探讨sublytic C5b-9刺激GMCs上调IRF-1表达可能涉及的信号转导通路。方法:以大鼠IRF-1启动子全长1700bp荧光素酶报告基因为模板,用DNA重组技术将大鼠IRF-1基因转录起始位点上游13000bp、600bp、200bp和100bp的启动子片段分别克隆入pGL3-Basic荧光素酶报告基因载体中,分别命名为:pGL3-Basic/IRF-1 promoter 1300bp、pGL3-Basic/IRF-1 promoter 600bp、pGL3-Basic/IRF-1 promoter 200bp和pGL3-Basic/IRF-1 promoter 100bp,酶切分析及序列测定正确后,用GenEscortTMIII转染试剂将上述各质粒以及pGL3-Basic/3×GAS荧光素酶报告基因分别与对照质粒PRL-SV40共转染大鼠GMCs细胞,转染后45h行sublytic C5b-9刺激,测定Sublytic C5b-9刺激组与其他各处理组的相对荧光活性。此外,利用Western blot检查Sublytic C5b-9刺激组与其他各对照组GMCs中一些信号通路相关蛋白,如信号传导蛋白和转录激活物(signal transducers and activators of transcription, STAT)、p-STAT1、p38、p-p38、C-Jun基末端激酶(c-Jun N-terminal kinase, JNK)、p-JNK、细胞外信号调节蛋白激酶(extra cellular signal-regulated protein kinase, ERK)和p-ERK的表达情况,同时分别应用JAK抑制剂(AG490)、p38抑制剂(SB203580)、JNK抑制剂(SP600125)和ERK抑制剂(PD98059)处理大鼠GMCs,然后检查上述抑制剂对sublytic C5b-9诱导大鼠GMCs表达p-STAT1和IRF-1蛋白的影响。结果:荧光素酶报告实验表明,转染pGL3-Basic/IRF-1 promoter 1700bp、pGL3-Basic/IRF-1 promoter 1300bp、pGL3-Basic/IRF-1 promoter 600bp和pGL3-Basic/IRF-1 promoter 200bp荧光素酶报告基因后再行sublytic C5b-9刺激的GMCs中的荧光素酶活性明显高于其他各对照组,转染pGL3-Basic/3×GAS荧光素酶报告基因的GMCs行sublytic C5b-9刺激后其荧光素酶活性升高较为显著,而转染pGL3-Basic/IRF-1 promoter 100bp荧光素酶报告基因的GMCs经sublytic C5b-9刺激后荧光素酶活性较其余对照组无明显差别。另Sublytic C5b-9刺激组GMCs中的p-STAT1、p-p38、p-JNK和p-ERK表达均较其余对照组明显上调。JAK抑制剂(AG490)可抑制sublytic C5b-9刺激GMCs后p-STAT1和IRF-1的表达量,p38抑制剂(SB203580)亦可使sublytic C5b-9刺激GMCs后p-STAT1和IRF-1的表达减少,而JNK抑制剂和ERK抑制剂对sublytic C5b-9刺激GMCs后IRF-1蛋白的表达量影响不显著。结论:Sublytic C5b-9刺激大鼠GMCs后可上调IRF-1基因启动子的活性,其中干扰素活化序列(IFN-gamma activated sequence, GAS)在sublytic C5b-9激活IRF-1基因转录中起着较大的作用,此外,sublytic C5b-9上调GMCs IRF-1基因表达可能与p38MAPK和JAK-STAT信号通路的活化存在一定的关系。
Part I The role of IRF-1 in the rat GMCs apoptosis induced by sublytic C5b-9
Objective: To investigate the effects of sublytic C5b-9 complexes on the production of interferon regulatory factor 1 (IRF-1), apoptosis of glomerular mesangial cells (GMCs) and Caspase activation. Then to explore the role of IRF-1 on the mechanism of sublytic C5b-9 mediating GMCs apoptosis and production of actived Caspase in vitro. Methods: Firstly, the rat GMCs were cultured and divided into different groups. The mRNA and protein levels of IRF-1 in GMCs with sublytic C5b-9 stimulation were measured by RT-PCR and Western blot. The GMCs apoptosis was evaluated by flow cytometry analysis. Meanwhile, the protein levels of cleaved Caspase 9,cleaved Caspase 8 and cleaved Caspase 3 were measured by Western blot. Moreover, the effects of IRF-1 overexpression by IRF-1 expression plasmid or knockdown by IRF-1 short hairpin RNA (shRNA) on the GMCs apoptosis were determined using the corresponding methods, and the production of actived Caspase induced by sublytic C5b-9 in IRF-1 knockdown GMCs were measured by Western blot. In addition, the number of GMCs apoptosis induced by sublytic C5b-9 or overexpression of IRF-1 were also measured when GMCs were pretreated with Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK). Results: In vitro, the IRF-1 expression, GMCs apoptosis and Caspase activation induced by sublytic C5b-9 could be increased, and IRF-1 can promote GMCs apoptosis induced by sublytic C5b-9. The number of GMCs apoptosis and the production of cleaved Caspase 8 and cleaved Caspase 3 protein were markedly reduced by IRF-1 knockdown. In addition, the number of GMCs apoptosis induced by sublytic C5b-9 or overexpression of IRF-1 could be markedly reduced by Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK). Conclusion: GMCs apoptosis mediated by sublytic C5b-9 in vitro is partially dependent on the up-regulation of IRF-1 expression and Caspase activation.
PartⅡThe inhibitory effect of silencing IRF-1 gene on the GMCs apoptosis and secondary proliferation of the rat with Thy-1 nephritis
[Abstract] Objective: To explore the inhibitory effects of silencing renal IRF-1 gene using shRNA on the GMCs apoptosis and secondary proliferation of rats with Thy-1 nephritis (Thy-1N). Methods: Firstly, an animal model of rat Thy-1N was induced by injecting anti-thymocyte serum (ATS). Then the expression of IRF-1 and actived Caspase in the renal tissue were observed at fixed time. Furthermore, rats were divided into different groups, and IRF-1 shRNA expressing plasmids, Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK) were transferred into different rat kidneys by renal artery perfusion followed by electroporation or by tail vein injection, and then Thy-1N was reproduced by injection of ATS. The protein levels of IRF-1 and cleaved Caspase 9, 8 and 3 in the renal tissue of different group rats were assessed by Western blot at 3h after ATS administration. Meanwhile, the renal histopathologic changes were observed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), electron microscopy (EM) and light microscope (LM). The total content of 24h urinary protein was also detected at 24h and 7d. Results: The expression of IRF-1 in the renal tissue was obviously increased at 3h in Thy-1N rats, and the expression of IRF-1 and cleaved Caspase 8 and 3 in the renal tissue transferred with IRF-1 shRNA followed by induction of Thy-1N was significantly reduced compared with Thy-1N model rats. TUNEL analysis and morphological observation under EM showed that the GMCs apoptosis in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were markedly reduced compared with Thy-1N model group. The secretion of 24h urinary protein in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were also less than that in Thy-1N model group or DMSO+Thy-1N group at 7d, and morphological observation under LM showed that the total number of glomerular cells in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were significantly decreased compared with Thy-1N model group. Conclusion: Silencing renal IRF-1 gene or inhibiting the Caspase activation can diminish the lessions of GMCs apoptosis including secondary proliferation of rats with Thy-1N.
Part III The role and signal pathway of triggering IRF-1 transcription or expression by sublytic C5b-9
[Abstract] Objective: To study the function of sublytic C5b-9 in IRF-1 transcription and to explore the probable signal pathway involved in it. Methods: Firstly, the 1300bp, 600bp, 200bp and 100bp fragments of rat IRF-1 promoter were amplified by PCR with pGL3-Basic/IRF-1 promoter 1700bp as a template and were directionally cloned into pGL3-Basic multiple cloning sites to construct the luciferase reporter plasmids, namely, pGL3-Basic/IRF-1 promoter 1300bp, pGL3- Basic/IRF-1 promoter 600bp, pGL3-Basic/IRF-1 promoter 200bp and pGL3-Basic/IRF-1 promoter 100bp. After being screened and comfirmed, the recombinant plasmids and pGL3-Basic/3×GAS were transfected into GMCs with PRL-SV40 respectively. Then the rat GMCs were divided into different groups, and calculate the relative luciferase activity unit (RLU) of each group. Secondly, the rat GMCs were cultured and divided into different groups, and the protein levels of signal transducers and activators of transcription (STAT), p-STAT1, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, extra cellular signal-regulated protein kinase (ERK) and p-ERK in GMCs with sublytic C5b-9 stimulation were measured by Western blot. The protein levels of p-STAT1 and IRF-1 in GMCs stimulated by sublytic C5b-9 in the present or absent of JAK inhibitor (AG490) and the protein levels of IRF-1 in GMCs stimulated by sublytic C5b-9 in the present or absent of p38 inhibitor (SB203580), JNK inhibitor (SP600125) and ERK inhibitor (U0126) were also detected by Western blot. At last, the protein levels of p-STAT1 in GMCs stimulated by sublytic C5b-9 in the present or absent of p38 inhibitor (SB203580) were measured by Western blot. Results: The luciferase analysis verified the IFN-gamma activated sequence (GAS) plays a major role in the induction of IRF-1 by sublytic C5b-9 attack, and the expression of p-STAT1 and IRF-1 can be downregulated using the JAK and p38 inhibitor. Conclusion: Sublytic C5b-9 can upregulation IRF-1 promoter activity in rat GMCs, which is relevant with the activation of p38MAPK and JAK-STAT pathways.
目的:体外探讨亚溶解型C5b-9(sublytic C5b-9)刺激大鼠肾小球系膜细胞(glomerular mesangial cells,GMCs)上调干扰素调节因子1(interferon regulatory factor 1, IRF-1)基因表达、并发凋亡现象以及半胱氨酸天冬氨酸特异性蛋白酶(Caspase)的活化情况,同时确定过表达或沉默IRF-1基因对sublytic C5b-9诱发大鼠GMCs凋亡病变的影响以及沉默IRF-1基因对cleaved Caspase 9、cleaved Caspase 8和cleaved Caspase 3蛋白表达的影响,同时,检查使用Caspase抑制剂对sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡现象的影响。方法:先体外培养大鼠GMCs并给予sublytic C5b-9刺激(实验设不同处理对照),用RT-PCR和Western blot分别检查受sublytic C5b-9刺激的GMCs上调IRF-1 mRNA的丰度及蛋白表达的水平,并用流式细胞术(Flow Cytometry, FCM)分析各组GMCs的凋亡情况,同时用Western blot检查sublytic C5b-9刺激的GMCs中Caspase的活化情况。然后,分别将构建的IRF-1过表达质粒和发夹式小干涉RNA(short hairpin RNA, shRNA)质粒转染GMCs,并将GMCs作相应的分组处理,定量分析各组GMCs的凋亡率,同时检查转染IRF-1 shRNA质粒的GMCs和对照组GMCs中cleaved Caspase 9、cleaved Caspase 8和cleaved Caspase 3蛋白的表达情况。此外,使用Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)处理大鼠GMCs,观察其对sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡病变的影响。结果:Sublytic C5b-9刺激大鼠GMCs早期可见IRF-1表达上调并伴随GMCs的凋亡以及Caspase的活化,过表达IRF-1可促进sublytic C5b-9刺激引起的GMCs凋亡病变,而用IRF-1 shRNA不仅可以使sublytic C5b-9刺激的GMCs的凋亡率下降,也可以减少sublytic C5b-9刺激的GMCs中上调cleaved Caspase 8和cleaved Caspase 3的表达量,但对cleaved Caspase 9表达的影响并不显著。此外,应用Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)亦可显著减轻由sublytic C5b-9刺激和过表达IRF-1引起的GMCs凋亡数量。结论:Sublytic C5b-9诱导的大鼠GMCs凋亡病变可能与其上调IRF-1表达及激活Caspase有一定的关系。
第二部分体内探讨沉默IRF-1基因对Thy-1N大鼠GMCs凋亡以及继发增生病变的抑制效应
目的:探讨用IRF-1 shRNA沉默大鼠肾组织内IRF-1基因对Thy-1肾炎(Thy-1 nephritis, Thy-1N)大鼠GMCs凋亡和继发增生病变的抑制作用。方法:首先,复制大鼠Thy-1N模型,定期采用RT-PCR和Western blot方法检查其肾组织中IRF-1和cleaved Caspase 9、8和3蛋白的表达情况。然后应用肾动脉灌注加电导入方法,将IRF-1 shRNA质粒导入大鼠肾组织,再经尾静脉注射注射抗胸腺细胞血清(anti-thymocyte serum,ATS)复制大鼠Thy-1N模型。同时尾静脉注射Caspase 8抑制剂(Z-IETD-FMK)和Caspase 3抑制剂(Z-DEVD-FMK)后再复制大鼠Thy-1N模型。分别取注射ATS后3h和7d时的大鼠肾组织,应用Western blot检查3h时肾组织中IRF-1蛋白的表达水平及cleaved Caspase 9、8和3蛋白的表达情况。此外,应用末端转移酶介导的dUTP缺口末端标记(terminal deoxynucleotidyl transferase dUTP nick end labeling, TUNEL)技术和电镜检查3h时肾组织的病理学改变。另光镜检查计数7d时肾小球内的细胞总数,并用生化方法测定各组大鼠24h和7d时尿蛋白总量的变化。结果:大鼠Thy-1N病变3h时,肾组织中IRF-1的表达水平明显升高。IRF-1 shRNA处理的Thy-1N大鼠(IRF-1 shRNA+Thy-1N组),其肾组织中IRF-1基因的表达以及Caspase 8和Caspase 3的活化水平显著低于Thy-1N模型组。另IRF-1 shRNA+Thy-1N组大鼠以及经Caspase抑制剂处理的大鼠(Z-IETD-FMK+Thy-1N组和Z-DEVD-FMK+Thy-1N组),3h时肾小球内GMCs凋亡数量显著减少。实验7d时,肾小球细胞的增生程度有所减轻,并且,24h尿蛋白的分泌量也明显减少。结论:沉默大鼠肾组织内IRF-1基因以及使用Caspase抑制剂均能明显减轻Thy-1N大鼠GMCs的凋亡病变及继发增生现象,包括尿蛋白的分泌。
第三部分体外研究sublytic C5b-9刺激大鼠GMCs启动IRF-1转录的作用及其信号通路
目的:研究sublytic C5b-9刺激大鼠GMCs启动IRF-1转录的作用,同时,探讨sublytic C5b-9刺激GMCs上调IRF-1表达可能涉及的信号转导通路。方法:以大鼠IRF-1启动子全长1700bp荧光素酶报告基因为模板,用DNA重组技术将大鼠IRF-1基因转录起始位点上游13000bp、600bp、200bp和100bp的启动子片段分别克隆入pGL3-Basic荧光素酶报告基因载体中,分别命名为:pGL3-Basic/IRF-1 promoter 1300bp、pGL3-Basic/IRF-1 promoter 600bp、pGL3-Basic/IRF-1 promoter 200bp和pGL3-Basic/IRF-1 promoter 100bp,酶切分析及序列测定正确后,用GenEscortTMIII转染试剂将上述各质粒以及pGL3-Basic/3×GAS荧光素酶报告基因分别与对照质粒PRL-SV40共转染大鼠GMCs细胞,转染后45h行sublytic C5b-9刺激,测定Sublytic C5b-9刺激组与其他各处理组的相对荧光活性。此外,利用Western blot检查Sublytic C5b-9刺激组与其他各对照组GMCs中一些信号通路相关蛋白,如信号传导蛋白和转录激活物(signal transducers and activators of transcription, STAT)、p-STAT1、p38、p-p38、C-Jun基末端激酶(c-Jun N-terminal kinase, JNK)、p-JNK、细胞外信号调节蛋白激酶(extra cellular signal-regulated protein kinase, ERK)和p-ERK的表达情况,同时分别应用JAK抑制剂(AG490)、p38抑制剂(SB203580)、JNK抑制剂(SP600125)和ERK抑制剂(PD98059)处理大鼠GMCs,然后检查上述抑制剂对sublytic C5b-9诱导大鼠GMCs表达p-STAT1和IRF-1蛋白的影响。结果:荧光素酶报告实验表明,转染pGL3-Basic/IRF-1 promoter 1700bp、pGL3-Basic/IRF-1 promoter 1300bp、pGL3-Basic/IRF-1 promoter 600bp和pGL3-Basic/IRF-1 promoter 200bp荧光素酶报告基因后再行sublytic C5b-9刺激的GMCs中的荧光素酶活性明显高于其他各对照组,转染pGL3-Basic/3×GAS荧光素酶报告基因的GMCs行sublytic C5b-9刺激后其荧光素酶活性升高较为显著,而转染pGL3-Basic/IRF-1 promoter 100bp荧光素酶报告基因的GMCs经sublytic C5b-9刺激后荧光素酶活性较其余对照组无明显差别。另Sublytic C5b-9刺激组GMCs中的p-STAT1、p-p38、p-JNK和p-ERK表达均较其余对照组明显上调。JAK抑制剂(AG490)可抑制sublytic C5b-9刺激GMCs后p-STAT1和IRF-1的表达量,p38抑制剂(SB203580)亦可使sublytic C5b-9刺激GMCs后p-STAT1和IRF-1的表达减少,而JNK抑制剂和ERK抑制剂对sublytic C5b-9刺激GMCs后IRF-1蛋白的表达量影响不显著。结论:Sublytic C5b-9刺激大鼠GMCs后可上调IRF-1基因启动子的活性,其中干扰素活化序列(IFN-gamma activated sequence, GAS)在sublytic C5b-9激活IRF-1基因转录中起着较大的作用,此外,sublytic C5b-9上调GMCs IRF-1基因表达可能与p38MAPK和JAK-STAT信号通路的活化存在一定的关系。
Part I The role of IRF-1 in the rat GMCs apoptosis induced by sublytic C5b-9
Objective: To investigate the effects of sublytic C5b-9 complexes on the production of interferon regulatory factor 1 (IRF-1), apoptosis of glomerular mesangial cells (GMCs) and Caspase activation. Then to explore the role of IRF-1 on the mechanism of sublytic C5b-9 mediating GMCs apoptosis and production of actived Caspase in vitro. Methods: Firstly, the rat GMCs were cultured and divided into different groups. The mRNA and protein levels of IRF-1 in GMCs with sublytic C5b-9 stimulation were measured by RT-PCR and Western blot. The GMCs apoptosis was evaluated by flow cytometry analysis. Meanwhile, the protein levels of cleaved Caspase 9,cleaved Caspase 8 and cleaved Caspase 3 were measured by Western blot. Moreover, the effects of IRF-1 overexpression by IRF-1 expression plasmid or knockdown by IRF-1 short hairpin RNA (shRNA) on the GMCs apoptosis were determined using the corresponding methods, and the production of actived Caspase induced by sublytic C5b-9 in IRF-1 knockdown GMCs were measured by Western blot. In addition, the number of GMCs apoptosis induced by sublytic C5b-9 or overexpression of IRF-1 were also measured when GMCs were pretreated with Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK). Results: In vitro, the IRF-1 expression, GMCs apoptosis and Caspase activation induced by sublytic C5b-9 could be increased, and IRF-1 can promote GMCs apoptosis induced by sublytic C5b-9. The number of GMCs apoptosis and the production of cleaved Caspase 8 and cleaved Caspase 3 protein were markedly reduced by IRF-1 knockdown. In addition, the number of GMCs apoptosis induced by sublytic C5b-9 or overexpression of IRF-1 could be markedly reduced by Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK). Conclusion: GMCs apoptosis mediated by sublytic C5b-9 in vitro is partially dependent on the up-regulation of IRF-1 expression and Caspase activation.
PartⅡThe inhibitory effect of silencing IRF-1 gene on the GMCs apoptosis and secondary proliferation of the rat with Thy-1 nephritis
[Abstract] Objective: To explore the inhibitory effects of silencing renal IRF-1 gene using shRNA on the GMCs apoptosis and secondary proliferation of rats with Thy-1 nephritis (Thy-1N). Methods: Firstly, an animal model of rat Thy-1N was induced by injecting anti-thymocyte serum (ATS). Then the expression of IRF-1 and actived Caspase in the renal tissue were observed at fixed time. Furthermore, rats were divided into different groups, and IRF-1 shRNA expressing plasmids, Caspase 8 inhibitor (Z-IETD-FMK) and Caspase 3 inhibitor (Z-DEVD-FMK) were transferred into different rat kidneys by renal artery perfusion followed by electroporation or by tail vein injection, and then Thy-1N was reproduced by injection of ATS. The protein levels of IRF-1 and cleaved Caspase 9, 8 and 3 in the renal tissue of different group rats were assessed by Western blot at 3h after ATS administration. Meanwhile, the renal histopathologic changes were observed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), electron microscopy (EM) and light microscope (LM). The total content of 24h urinary protein was also detected at 24h and 7d. Results: The expression of IRF-1 in the renal tissue was obviously increased at 3h in Thy-1N rats, and the expression of IRF-1 and cleaved Caspase 8 and 3 in the renal tissue transferred with IRF-1 shRNA followed by induction of Thy-1N was significantly reduced compared with Thy-1N model rats. TUNEL analysis and morphological observation under EM showed that the GMCs apoptosis in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were markedly reduced compared with Thy-1N model group. The secretion of 24h urinary protein in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were also less than that in Thy-1N model group or DMSO+Thy-1N group at 7d, and morphological observation under LM showed that the total number of glomerular cells in IRF-1 shRNA+Thy-1N group, Z-IETD-FMK+Thy-1N group and Z-DEVD-FMK+Thy-1N group were significantly decreased compared with Thy-1N model group. Conclusion: Silencing renal IRF-1 gene or inhibiting the Caspase activation can diminish the lessions of GMCs apoptosis including secondary proliferation of rats with Thy-1N.
Part III The role and signal pathway of triggering IRF-1 transcription or expression by sublytic C5b-9
[Abstract] Objective: To study the function of sublytic C5b-9 in IRF-1 transcription and to explore the probable signal pathway involved in it. Methods: Firstly, the 1300bp, 600bp, 200bp and 100bp fragments of rat IRF-1 promoter were amplified by PCR with pGL3-Basic/IRF-1 promoter 1700bp as a template and were directionally cloned into pGL3-Basic multiple cloning sites to construct the luciferase reporter plasmids, namely, pGL3-Basic/IRF-1 promoter 1300bp, pGL3- Basic/IRF-1 promoter 600bp, pGL3-Basic/IRF-1 promoter 200bp and pGL3-Basic/IRF-1 promoter 100bp. After being screened and comfirmed, the recombinant plasmids and pGL3-Basic/3×GAS were transfected into GMCs with PRL-SV40 respectively. Then the rat GMCs were divided into different groups, and calculate the relative luciferase activity unit (RLU) of each group. Secondly, the rat GMCs were cultured and divided into different groups, and the protein levels of signal transducers and activators of transcription (STAT), p-STAT1, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, extra cellular signal-regulated protein kinase (ERK) and p-ERK in GMCs with sublytic C5b-9 stimulation were measured by Western blot. The protein levels of p-STAT1 and IRF-1 in GMCs stimulated by sublytic C5b-9 in the present or absent of JAK inhibitor (AG490) and the protein levels of IRF-1 in GMCs stimulated by sublytic C5b-9 in the present or absent of p38 inhibitor (SB203580), JNK inhibitor (SP600125) and ERK inhibitor (U0126) were also detected by Western blot. At last, the protein levels of p-STAT1 in GMCs stimulated by sublytic C5b-9 in the present or absent of p38 inhibitor (SB203580) were measured by Western blot. Results: The luciferase analysis verified the IFN-gamma activated sequence (GAS) plays a major role in the induction of IRF-1 by sublytic C5b-9 attack, and the expression of p-STAT1 and IRF-1 can be downregulated using the JAK and p38 inhibitor. Conclusion: Sublytic C5b-9 can upregulation IRF-1 promoter activity in rat GMCs, which is relevant with the activation of p38MAPK and JAK-STAT pathways.
引文
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