腺病毒介导的反义细胞外信号调节激酶2基因治疗抑制肾小管上皮—间充质转化并延缓大鼠移植肾肾病
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摘要
目的：探讨细胞外信号调节激酶2(extracellular signal regulated kinase 2，ERK2)对肾小管上皮细胞向间充质转化的调控效应；建立大鼠肾移植模型，探讨腺病毒介导的反义ERK2(Adenovirus-mediated antisense ERK2，Adanti-ERK2)对大鼠移植肾肾病的延缓作用。
方法：(1)构建反义ERK2腺病毒载体Adanti-ERK2及对照病毒Ad-LacZ。(2)以结缔组织生长因子(connective tissue growth factor，CTGF)刺激肾小管上皮细胞，观测肾小管上皮细胞表型变化及ERK2蛋白表达情况。(3)Adanti-ERK2按不同转染强度(multiplicity of infection，MOI)转染肾小管上皮细胞，确定最适转染强度。按干预因素不同将肾小管上皮细胞分为对照组(无干预因素)、Ad-LacZ组(最适MOI的Ad-LacZ)、CTGF组(加入终浓度为5ng／ml的CTGF)和Adanti-ERK2组(加入终浓度为5ng／ml的CTGF和最适MOI的Adanti-ERK2)。将肾小管上皮细胞培养72h后，细胞免疫化学法检测各组上皮细胞表型蛋白E-Cadherin和间充质细胞表型蛋白Vimentin、α-SMA的表达，Western blot法检测各组ERK2蛋白的表达；Boyden小室在第一、三和第五天检测各组肾小管上皮细胞迁移能力的变化。(4)建立Fisher344大鼠至Lewis大鼠的慢性移植肾肾病(chronic allograft nephropathy，CAN)模型。按不同干预因素将受体大鼠分为对照组、Ad-LacZ组和Adanti-ERK2组。在移植前，对照组供肾给予HTK液灌注；Ad-LacZ组给予含有1×10~9pfu Ad-LacZ的HTK液灌注；Adanti-ERK2组给予含有1×10~9pfu Adanti-ERK2的HTK液灌注。在移植术后24周，取移植肾脏进行病理学观察；免疫组织化学法检测肾小管上皮细胞E-Cadherin、Vimentin、α-SMA和TβRI的表达以及CD4~+T、CD8~+T、ED-1~+细胞的间质浸润情况；ELISA法检测血清中TGF-β1的含量。
结果：(1)成功地构建了反义ERK2和LacZ腺病毒载体。(2)肾小管上皮细胞在CTGF刺激72h后，上皮细胞表型E-Cadherin表达减少，而间充质细胞表型蛋白Vimentin和α-SMA表达增加，肾小管上皮细胞在CTGF的作用下转化为间充质细胞。在CTGF刺激肾小管上皮细胞表型转化过程中伴随有ERK2蛋白的表达上调。(3)与MOI为50和200相比较，腺病毒载体以转染强度100转染肾小管上皮细胞2天后，有95％的细胞表达绿色荧光；并且在转染后第一天和第二天，细胞存活率与对照组和MOI 50组无显著差异，确定最适MOI值为100。(4)Adanti-ERK2组以Adanti-ERK2(MOI 100)转染组肾小管上皮细胞后，在CTGF刺激下其上皮细胞表型蛋白E-Cadherin表达较对照组未发生明显的变化，Vimentin和α-SMA的表达较CTGF组明显减少；同时伴有ERK2蛋白表达的下调。(5)Boyden小室检测发现，各组细胞在第一天迁移至滤膜对侧的细胞数目无差异；在第三天CTGF组细胞迁移数开始高于其他三组；在第五天迁移出细胞数明显高于其他各组(CTGF组VS对照组，Ad-LacZ组和Adanti-ERK2组：45．1±1．9 VS12．7±1．4，11．6±1．7和14．6±1．6；P＜0．05)，而Adanti-ERK2组与对照组和Ad-LacZ组间差异无统计学意义(Adanti-ERK2组VS对照组：14．6±1．6 VS 12．7±1．4，P＞0．05；Adanti-ERK2组VSAd-LacZ组：14．6±1．6 VS 11．6±1．7，P＞0．05)。(6)大鼠肾移植受体鼠在移植术后24周，对照组和Ad-LacZ组移植肾呈现典型的CAN表现，间质中CD4~+T、CD8~+T和ED-1~+细胞的浸润明显。在Adanti-ERK2组移植肾肾小球硬化不明显，间质纤维化病变轻微，间质内有少量CD4~+T、CD8~+T、ED-1~+细胞的浸润。(7)在受体鼠移植术后24周，对照组和Ad-LacZ组移植肾病变区，肾小管上皮细胞E-Cadherin表达减少(对照组VS Adanti-ERK2组：71．6±6．1 VS 160．7±11．1；P＜0．05)肾间质内Vimentin(对照组VS Adanti-ERK2组：110．3±7．2 VS 47．8±6．5；P＜0．05)和α-SMA表达显著增多。Adanti-ERK2组移植肾小管上皮细胞E-Cadherin表达基本正常，Vimentin和α-SMA表达未见明显的增多。(8)在移植术后24周，对照组和Ad-LacZ组血清中TGF-β1含量明显高于Adanti-ERK2组，同时移植肾组织中伴有TβR I(对照组VSAdanti-ERK2组：146．4±10．2 VS 82．6±6．5；P＜0．05)表达增加。
结论：肾小管上皮细胞通过上皮—间充质转化途径增加了肌成纤维细胞的来源，其对移植肾术后纤维化的进程有着重要的意义。在体外，CTGF可以诱导肾小管上皮细胞发生向间充质细胞转化，以腺病毒介导的反义ERK2基因治疗可以有效地阻断CTGF诱导的肾小管上皮细胞向间充质细胞转化；ERK2信号转导通路对CTGF诱导的肾小管上皮-间充质转化有调控作用。在体内以腺病毒介导的反义ERK2的基因治疗可以延缓移植肾肾病的进展，对移植肾具有保护作用。这种保护机制可能与减少炎性细胞的浸润、下调TGF-β1等致纤维化因子及其受体的表达以及抑制肾小管上皮细胞向间充质细胞的转化有关。针对ERK2信号转导通路的基因治疗为防治肾脏纤维化提供可能的新的治疗靶点。
Objective: To investigate the ERK2 signal pass way on Epithelial Mesenchymal Transition in vitro and in vivo and the effects of Adanti-ERK2 attenuated CAN in kidney allografts was well examined.
Methods: (1) The Adanti-ERK2 and Ad-LacZ were generated. (2)The renal tubular epithelial cells were transfected by Ad-antiERK2 with multiplicity of infection (MOI) 50, 100 and 200 for 1h, followed by the green fluorescence observation 2 days later. The live cells ratio was detected 24h and 48h later. (3)The cultured renal tubular epithelial cells were divided into four groups: control group (no gene transfer); Ad-LacZ group (transfected with Ad-LacZ); CTGF-treated group (treated with CTGF at a final concentration of 5 ng/ml); and Adanti-ERK2 group (treated with CTGF at a final concentration of 5 ng/ml and Adanti-ERK2 with moderate MOI). The cells were collected at 72h time points. Immunohistochemistry was used to detect the E-Cadherin, Vimentin andα-SMA; Western-blot was used to detect the ERK2 in cells. Boyden Chamber was used to detect the migration of the renal tubular epithelial cells at 1d, 3d and 5d. (4)Male Lewis (LEW, RT11) rat received male Fisher (F344, RT11v1) renal allograft. The recipients were divided into three groups: control group; Ad-LacZ group and Adanti-ERK2 group. All recipients were sacrificed for grafts and serum at 24 weeks after transplantation. Morphometric analysis was used to determine the fibrosis of grafts. Immunohistochemistry was used to detect the expression of E-Cadherin, Vimentin,α-SMA and TβRⅠ. The infiltration of CD4~+ T, CD8~+ T lymphocyte and ED-1~+ monocytes was well detected in the same way. ELISA was used to detect TGF-β1 in serum.
Results: (1) Over 95% renal tubular epithelial cells expressed green fluorescence aftertransfected by Ad-antiERK2 (MOI 100) for 2 days. The live cell ratio at 2 and 4 days had nodifference from those of the control group. So the moderate MOI was 100. (2) Comparedwith CTGF-treated group, there were more E-Cadherin, and less Vimentin expressed in thecell of Adanti-ERK2 group. Theα-SMA was detected in the cells of CTGF-treated group.For the expression of E-Cadherin, Vimentin,α-SMA, there were no diference between theAdanti-ERK2 group with the control and the Ad-LacZ groups. (3)On the first two days, themigration of renal tubular epithelial cells in the four groups was no difference, there were nocells migrated through the pores to the opposite side of the transwell filters. Since from 3d,the transformed cells began to migrate through the pores to the opposite side of filters in theCTGF-treated group. In the 5d, compared with CTGF-treated group, there were markedlyless transformed cells in the opposite side of filters in Adanti-ERK2 group. (4)The grafts incontrol group and Ad-LacZ group showed with CAN. There were less E-Cadherin in renaltubular epithelial cells in control group but more Vimentin andα-SMA. In Adanti-ERK2group, the fibrosis was ameliorated and less T lymphocytes and ED-1~+ monocytes infiltratedin the interstitium. The expression of E-Cadherin was no markedly difference inAdanti-ERK2 group and in normal rats. (5)Compared with the control groups, theexpression of TGF-β1 and TβR I in Adanti-ERK2 group were down-regulated.
Conclusions: Epithelial-Mesenchymal transition (EMT) plays an important role in the progress of chronic allograft nephropathy (CAN). In vitro, Adanti-ERK2 gene therapy can prevent CTGF induing Epithelial Mesenchymal Transition of renal tubular epithelial cells. In vivo, Adanti-ERK2 gene therapy protects renal allograft and attenuates graft fibrosis, which may be correlated with the decreased renal tubular epithelial mesenchymal transition, the decreased infiltration of CD4~+ T lymphocyte, CD8~+ T lymphocyte and ED-1~+ monocytes in renal interstitium, and the down-regulated TGF-(31 expression. In conclusion, our results suggest Adanti-ERK2 gene therapy inhibits tubular EMT both in vitro and in vivo, and attenuates CAN in kidney allografts. It is possible to develop elaborate molecular drug(s) to treat CAN in the future, as the ERK signaling pathway may be a promising novel efficient therapeutic target.
方法：(1)构建反义ERK2腺病毒载体Adanti-ERK2及对照病毒Ad-LacZ。(2)以结缔组织生长因子(connective tissue growth factor，CTGF)刺激肾小管上皮细胞，观测肾小管上皮细胞表型变化及ERK2蛋白表达情况。(3)Adanti-ERK2按不同转染强度(multiplicity of infection，MOI)转染肾小管上皮细胞，确定最适转染强度。按干预因素不同将肾小管上皮细胞分为对照组(无干预因素)、Ad-LacZ组(最适MOI的Ad-LacZ)、CTGF组(加入终浓度为5ng／ml的CTGF)和Adanti-ERK2组(加入终浓度为5ng／ml的CTGF和最适MOI的Adanti-ERK2)。将肾小管上皮细胞培养72h后，细胞免疫化学法检测各组上皮细胞表型蛋白E-Cadherin和间充质细胞表型蛋白Vimentin、α-SMA的表达，Western blot法检测各组ERK2蛋白的表达；Boyden小室在第一、三和第五天检测各组肾小管上皮细胞迁移能力的变化。(4)建立Fisher344大鼠至Lewis大鼠的慢性移植肾肾病(chronic allograft nephropathy，CAN)模型。按不同干预因素将受体大鼠分为对照组、Ad-LacZ组和Adanti-ERK2组。在移植前，对照组供肾给予HTK液灌注；Ad-LacZ组给予含有1×10~9pfu Ad-LacZ的HTK液灌注；Adanti-ERK2组给予含有1×10~9pfu Adanti-ERK2的HTK液灌注。在移植术后24周，取移植肾脏进行病理学观察；免疫组织化学法检测肾小管上皮细胞E-Cadherin、Vimentin、α-SMA和TβRI的表达以及CD4~+T、CD8~+T、ED-1~+细胞的间质浸润情况；ELISA法检测血清中TGF-β1的含量。
结果：(1)成功地构建了反义ERK2和LacZ腺病毒载体。(2)肾小管上皮细胞在CTGF刺激72h后，上皮细胞表型E-Cadherin表达减少，而间充质细胞表型蛋白Vimentin和α-SMA表达增加，肾小管上皮细胞在CTGF的作用下转化为间充质细胞。在CTGF刺激肾小管上皮细胞表型转化过程中伴随有ERK2蛋白的表达上调。(3)与MOI为50和200相比较，腺病毒载体以转染强度100转染肾小管上皮细胞2天后，有95％的细胞表达绿色荧光；并且在转染后第一天和第二天，细胞存活率与对照组和MOI 50组无显著差异，确定最适MOI值为100。(4)Adanti-ERK2组以Adanti-ERK2(MOI 100)转染组肾小管上皮细胞后，在CTGF刺激下其上皮细胞表型蛋白E-Cadherin表达较对照组未发生明显的变化，Vimentin和α-SMA的表达较CTGF组明显减少；同时伴有ERK2蛋白表达的下调。(5)Boyden小室检测发现，各组细胞在第一天迁移至滤膜对侧的细胞数目无差异；在第三天CTGF组细胞迁移数开始高于其他三组；在第五天迁移出细胞数明显高于其他各组(CTGF组VS对照组，Ad-LacZ组和Adanti-ERK2组：45．1±1．9 VS12．7±1．4，11．6±1．7和14．6±1．6；P＜0．05)，而Adanti-ERK2组与对照组和Ad-LacZ组间差异无统计学意义(Adanti-ERK2组VS对照组：14．6±1．6 VS 12．7±1．4，P＞0．05；Adanti-ERK2组VSAd-LacZ组：14．6±1．6 VS 11．6±1．7，P＞0．05)。(6)大鼠肾移植受体鼠在移植术后24周，对照组和Ad-LacZ组移植肾呈现典型的CAN表现，间质中CD4~+T、CD8~+T和ED-1~+细胞的浸润明显。在Adanti-ERK2组移植肾肾小球硬化不明显，间质纤维化病变轻微，间质内有少量CD4~+T、CD8~+T、ED-1~+细胞的浸润。(7)在受体鼠移植术后24周，对照组和Ad-LacZ组移植肾病变区，肾小管上皮细胞E-Cadherin表达减少(对照组VS Adanti-ERK2组：71．6±6．1 VS 160．7±11．1；P＜0．05)肾间质内Vimentin(对照组VS Adanti-ERK2组：110．3±7．2 VS 47．8±6．5；P＜0．05)和α-SMA表达显著增多。Adanti-ERK2组移植肾小管上皮细胞E-Cadherin表达基本正常，Vimentin和α-SMA表达未见明显的增多。(8)在移植术后24周，对照组和Ad-LacZ组血清中TGF-β1含量明显高于Adanti-ERK2组，同时移植肾组织中伴有TβR I(对照组VSAdanti-ERK2组：146．4±10．2 VS 82．6±6．5；P＜0．05)表达增加。
结论：肾小管上皮细胞通过上皮—间充质转化途径增加了肌成纤维细胞的来源，其对移植肾术后纤维化的进程有着重要的意义。在体外，CTGF可以诱导肾小管上皮细胞发生向间充质细胞转化，以腺病毒介导的反义ERK2基因治疗可以有效地阻断CTGF诱导的肾小管上皮细胞向间充质细胞转化；ERK2信号转导通路对CTGF诱导的肾小管上皮-间充质转化有调控作用。在体内以腺病毒介导的反义ERK2的基因治疗可以延缓移植肾肾病的进展，对移植肾具有保护作用。这种保护机制可能与减少炎性细胞的浸润、下调TGF-β1等致纤维化因子及其受体的表达以及抑制肾小管上皮细胞向间充质细胞的转化有关。针对ERK2信号转导通路的基因治疗为防治肾脏纤维化提供可能的新的治疗靶点。
Objective: To investigate the ERK2 signal pass way on Epithelial Mesenchymal Transition in vitro and in vivo and the effects of Adanti-ERK2 attenuated CAN in kidney allografts was well examined.
Methods: (1) The Adanti-ERK2 and Ad-LacZ were generated. (2)The renal tubular epithelial cells were transfected by Ad-antiERK2 with multiplicity of infection (MOI) 50, 100 and 200 for 1h, followed by the green fluorescence observation 2 days later. The live cells ratio was detected 24h and 48h later. (3)The cultured renal tubular epithelial cells were divided into four groups: control group (no gene transfer); Ad-LacZ group (transfected with Ad-LacZ); CTGF-treated group (treated with CTGF at a final concentration of 5 ng/ml); and Adanti-ERK2 group (treated with CTGF at a final concentration of 5 ng/ml and Adanti-ERK2 with moderate MOI). The cells were collected at 72h time points. Immunohistochemistry was used to detect the E-Cadherin, Vimentin andα-SMA; Western-blot was used to detect the ERK2 in cells. Boyden Chamber was used to detect the migration of the renal tubular epithelial cells at 1d, 3d and 5d. (4)Male Lewis (LEW, RT11) rat received male Fisher (F344, RT11v1) renal allograft. The recipients were divided into three groups: control group; Ad-LacZ group and Adanti-ERK2 group. All recipients were sacrificed for grafts and serum at 24 weeks after transplantation. Morphometric analysis was used to determine the fibrosis of grafts. Immunohistochemistry was used to detect the expression of E-Cadherin, Vimentin,α-SMA and TβRⅠ. The infiltration of CD4~+ T, CD8~+ T lymphocyte and ED-1~+ monocytes was well detected in the same way. ELISA was used to detect TGF-β1 in serum.
Results: (1) Over 95% renal tubular epithelial cells expressed green fluorescence aftertransfected by Ad-antiERK2 (MOI 100) for 2 days. The live cell ratio at 2 and 4 days had nodifference from those of the control group. So the moderate MOI was 100. (2) Comparedwith CTGF-treated group, there were more E-Cadherin, and less Vimentin expressed in thecell of Adanti-ERK2 group. Theα-SMA was detected in the cells of CTGF-treated group.For the expression of E-Cadherin, Vimentin,α-SMA, there were no diference between theAdanti-ERK2 group with the control and the Ad-LacZ groups. (3)On the first two days, themigration of renal tubular epithelial cells in the four groups was no difference, there were nocells migrated through the pores to the opposite side of the transwell filters. Since from 3d,the transformed cells began to migrate through the pores to the opposite side of filters in theCTGF-treated group. In the 5d, compared with CTGF-treated group, there were markedlyless transformed cells in the opposite side of filters in Adanti-ERK2 group. (4)The grafts incontrol group and Ad-LacZ group showed with CAN. There were less E-Cadherin in renaltubular epithelial cells in control group but more Vimentin andα-SMA. In Adanti-ERK2group, the fibrosis was ameliorated and less T lymphocytes and ED-1~+ monocytes infiltratedin the interstitium. The expression of E-Cadherin was no markedly difference inAdanti-ERK2 group and in normal rats. (5)Compared with the control groups, theexpression of TGF-β1 and TβR I in Adanti-ERK2 group were down-regulated.
Conclusions: Epithelial-Mesenchymal transition (EMT) plays an important role in the progress of chronic allograft nephropathy (CAN). In vitro, Adanti-ERK2 gene therapy can prevent CTGF induing Epithelial Mesenchymal Transition of renal tubular epithelial cells. In vivo, Adanti-ERK2 gene therapy protects renal allograft and attenuates graft fibrosis, which may be correlated with the decreased renal tubular epithelial mesenchymal transition, the decreased infiltration of CD4~+ T lymphocyte, CD8~+ T lymphocyte and ED-1~+ monocytes in renal interstitium, and the down-regulated TGF-(31 expression. In conclusion, our results suggest Adanti-ERK2 gene therapy inhibits tubular EMT both in vitro and in vivo, and attenuates CAN in kidney allografts. It is possible to develop elaborate molecular drug(s) to treat CAN in the future, as the ERK signaling pathway may be a promising novel efficient therapeutic target.
引文
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