卡托普利对大鼠肾缺血—再灌注损伤的影响及其机制研究
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摘要
研究背景:肾脏为血液高灌注器官,对缺血及缺血-再灌注均敏感。肾缺血-再灌注损伤(I/R)可导致急性肾小管坏死甚至急性肾功能不全。目前,研究认为,肾I/R的病理生理机制非常复杂,涉及多种因素参与,其中炎症反应发生是重要因素。而炎症介质的产生和分布又与组织内补体系统的活化有密切的联系。在治疗肾缺血-再灌注损伤过程,人们常常使用血管紧张素转换酶抑制剂如卡托普利。希望通过扩张血管尽早恢复血流,减少缺血时间,防止肾缺血再灌注损伤的发生。
目的:本研究从探讨肾缺血再灌注损伤的机制出发,分析缺血再灌注损伤的关键因素以及血管紧张素转换酶抑制剂卡托普利通过何种机制而对肾缺血再灌注损伤起保护作用。
方法:本研究采用结扎—侧大鼠肾血管制备缺血-再灌注损伤模型,通过生化分析检测肾功能Scr、BUN值,应用病理形态学和免疫组织化学观察肾组织变化和相应靶蛋白表达,同时采用ELISA检测肾组织和血清中炎症细胞因子IL-6、TNF-α等变化,再应用RT-PCR检测不同时间炎症介质IL-1β、TNF-α的表达。通过磷酸化抗体、Western blot分析炎症信号通路中MAPK信号通路的活化程度。比浊法分析血清中补体量的变化。
结果:①发现大鼠缺血-再灌注损伤1h后,Scr、BUN值开始升高;再灌注2h后,Scr、BUN值明显上升。②缺血30min再灌注1h后,肾小球有炎性细胞浸润;缺血30min再灌注2h后,肾小管损害加重,细胞坏死,肾间质有大量炎性细胞浸润。③肾缺血-再灌注损伤中,假手术组以及缺血-再灌注不同时间组,血清中炎症细胞因子IL-6、TNF-α等的水平无显著变化。而肾组织中炎症细胞因子IL-6、TNF-α等水平在肾缺血-再灌注1h、2h后明显升高。缺血30min再灌注1h后,炎症介质基因IL-1β、TNF-α的mRNA水平明显上调。④Westernblot结果显示,当肾脏缺血30min,肾组织还无灌注时,MAPK信号通路中p38、ERK、JNK通路出现激活。随着再灌注时间的延长增加,P38、ERK和JNK明显磷酸化(激活)。当再灌注30min时,MAPK的磷酸化程度较显著,但随着再灌注时间的延长,MAPK的磷酸化程度无明显改变。⑤卡托普利(血管紧张素转换酶抑制剂)治疗缺血-再灌注损伤后,其BUN、Scr值明显降低,肾小球内炎性细胞浸润明显减少,近端及皮髓交界处的肾小管上皮细胞肿胀减轻。同时肾组织中炎症细胞因子IL-6等水平降低。但是应用卡托普利治疗后肾组织中JNK、ERK、P38磷酸化程度仍然较高,与缺血-再灌注损伤组比较无明显差异。⑥肾组织再灌注时血清中补体总活性(CH50)出现明显降低,而卡托普利治疗后血清中补体总活性明显恢复。免疫细胞化学发现,缺血30min再灌注60min后,近端及皮髓交界处的肾小管上皮细胞基底部有补体活化片段C_(3d)沉积,卡托普利治疗后补体活化片段C_(3d)数量和程度明显减低。western blot分析补体C_3活化时的活性片段C_(3d)的表达发现,当经缺血-再灌注损伤(I/R组)后。肾组织中出现补体C_3的活性片段C_(3d),而经过卡托普利治疗(CAP组)后肾组织中活性片段C_(3d)表达量降低。
结论:肾缺血-再灌注损伤可导致炎性细胞因子在组织中表达增多。肾缺血再灌注损伤可导致组织中MAPK信号通路激活。卡托普利不影响MAPK炎症信号通路激活。但卡托普利可影响补体系统激活,进而抑制肾组织局部炎症细胞因子的表达而减轻缺血再灌注对肾组织的损伤。
Background:Kidney belongs to hyper-transfusion organ,and is very sensitive to ischemia or hypoxia.Renal ischemia reperfusion(I/R) injury can lead to acute tubular necrosis or acute renal insufficiency.At present,the studies show that pathophysiological mechanism of renal I/ R is extremely complex and is related to various factors,of which inflammatory response is important factor.The generation and distribution of inflammatory mediators have close connection with the activation of complement system.Angiotensin-converting enzyme inhibitors,such as captopril,are commonly used to treat renal I/R injury. Through the expansion of blood vessels,the blood flow is thus restored as soon as possible to reduce the ischemic time and prevent renal I/R injury.
Objective:To investigate the mechanism of renal I/R injury and its key factors,and analyze how angiotensin-converting enzyme inhibitor (captopril) have a protective effect on renal I/R injury.
Methods:In this study,I/R model was made through ligating one side renal vessel.Renal function indexes including Scr and BUN were detected through biochemical analysis;renal tissue and the corresponding protein expression were observed by pathomorphology and immunohistochemistry.At the same time,ELISA detection was used to determined inflammatory cytokines IL-6 and TNF-αin renal tissue and serum.IL-1β,TNF-αexpression and activation of MAPK signaling pathway were analyzed by RT-PCR and Western blot respectively. Turbidimetry was applied to essay serum complement.
Results:After I/R for 1 h,Scr and BUN value started to increase, and presented significantly after 2 h.Inflammatory cell infiltration was found in renal glomeruli during reperfusion for 1 h after ischemia for 30 min;while 30 min of ischemia followed by 2 h of reperfusion, deterioration of renal tubular damage with cell necrosis was observed, and a large number of inflammatory cells was infiltrated in renal interstitium.However,the levels of inflammatory cytokines IL-6 and TNF-αin serum had no significant difference between sham group and I/ R groups for different times.The contents of IL-6 and TNF-αin renal tissue treated with I/R injury for 1 h or 2 h significantly increased compared with sham group.While reperfusion for 1 h after ischemia for 30 min,the mRNA levels of inflammatory cytokines IL-6,TNF-αwere obviously up-regulated.
Western blot showed that when the renal ischemia for 30 min and without reperfusion,p38,ERK,JNK in MAPK signaling pathway were activated.With the extending of reperfusion time,p38,ERK and JNK were phosphorylated significantly(activated).At 30 min of reperfusion, MAPK phosphorylation was increased significantly,but then had no obvious change with the time of reperfusion.
In addition,we found that BUN and Scr values were decreased markedly after treatment of renal I/R injury with captopril(angiotensin inhibitors),inflammatory cell infiltration in renal glomeruli was significantly reduced,and swelling of tubular epithelial cells on the proximal and juxtamedullary regions was decreased.At the same time, the level of inflammatory cytokines IL-6 in renal tissue was reduced. However,after treatment with captopril,the JNK,ERK and P38 phosphorylation in renal tissue was still high,which had no significant difference with I/R group.
The serum complement activity(CH50) was significantly reduced during renal I/R injury,while recovered obviously after treatment with captopril.Immunocytochemistry revealed that 30 min of ischemia followed by 1 h of reperfusion,the depositions of complement activation fragment C3d were found at the basilar part of tubular epithelial cells on the proximal and juxtamedullary regions,which in amount or degree were degraded when treated with captopril.Western blot analysis indicated that activation fragment of complement C3(C3d) was observed in renal tissue after I/R injury(I/R group),and decreased after captopril treatment (CAP group).
Conclusion:Renal I/R injury can lead to increased expression of pro-inflammatory cytokines in the tissues,and can activate MAPK signaling pathway.Captopril affects the activation of complement system rather than MAPK inflammatory signaling pathway,and thus lessens I/R injury of renal tissue through inhibiting expression of some inflammatory cytokines.
目的:本研究从探讨肾缺血再灌注损伤的机制出发,分析缺血再灌注损伤的关键因素以及血管紧张素转换酶抑制剂卡托普利通过何种机制而对肾缺血再灌注损伤起保护作用。
方法:本研究采用结扎—侧大鼠肾血管制备缺血-再灌注损伤模型,通过生化分析检测肾功能Scr、BUN值,应用病理形态学和免疫组织化学观察肾组织变化和相应靶蛋白表达,同时采用ELISA检测肾组织和血清中炎症细胞因子IL-6、TNF-α等变化,再应用RT-PCR检测不同时间炎症介质IL-1β、TNF-α的表达。通过磷酸化抗体、Western blot分析炎症信号通路中MAPK信号通路的活化程度。比浊法分析血清中补体量的变化。
结果:①发现大鼠缺血-再灌注损伤1h后,Scr、BUN值开始升高;再灌注2h后,Scr、BUN值明显上升。②缺血30min再灌注1h后,肾小球有炎性细胞浸润;缺血30min再灌注2h后,肾小管损害加重,细胞坏死,肾间质有大量炎性细胞浸润。③肾缺血-再灌注损伤中,假手术组以及缺血-再灌注不同时间组,血清中炎症细胞因子IL-6、TNF-α等的水平无显著变化。而肾组织中炎症细胞因子IL-6、TNF-α等水平在肾缺血-再灌注1h、2h后明显升高。缺血30min再灌注1h后,炎症介质基因IL-1β、TNF-α的mRNA水平明显上调。④Westernblot结果显示,当肾脏缺血30min,肾组织还无灌注时,MAPK信号通路中p38、ERK、JNK通路出现激活。随着再灌注时间的延长增加,P38、ERK和JNK明显磷酸化(激活)。当再灌注30min时,MAPK的磷酸化程度较显著,但随着再灌注时间的延长,MAPK的磷酸化程度无明显改变。⑤卡托普利(血管紧张素转换酶抑制剂)治疗缺血-再灌注损伤后,其BUN、Scr值明显降低,肾小球内炎性细胞浸润明显减少,近端及皮髓交界处的肾小管上皮细胞肿胀减轻。同时肾组织中炎症细胞因子IL-6等水平降低。但是应用卡托普利治疗后肾组织中JNK、ERK、P38磷酸化程度仍然较高,与缺血-再灌注损伤组比较无明显差异。⑥肾组织再灌注时血清中补体总活性(CH50)出现明显降低,而卡托普利治疗后血清中补体总活性明显恢复。免疫细胞化学发现,缺血30min再灌注60min后,近端及皮髓交界处的肾小管上皮细胞基底部有补体活化片段C_(3d)沉积,卡托普利治疗后补体活化片段C_(3d)数量和程度明显减低。western blot分析补体C_3活化时的活性片段C_(3d)的表达发现,当经缺血-再灌注损伤(I/R组)后。肾组织中出现补体C_3的活性片段C_(3d),而经过卡托普利治疗(CAP组)后肾组织中活性片段C_(3d)表达量降低。
结论:肾缺血-再灌注损伤可导致炎性细胞因子在组织中表达增多。肾缺血再灌注损伤可导致组织中MAPK信号通路激活。卡托普利不影响MAPK炎症信号通路激活。但卡托普利可影响补体系统激活,进而抑制肾组织局部炎症细胞因子的表达而减轻缺血再灌注对肾组织的损伤。
Background:Kidney belongs to hyper-transfusion organ,and is very sensitive to ischemia or hypoxia.Renal ischemia reperfusion(I/R) injury can lead to acute tubular necrosis or acute renal insufficiency.At present,the studies show that pathophysiological mechanism of renal I/ R is extremely complex and is related to various factors,of which inflammatory response is important factor.The generation and distribution of inflammatory mediators have close connection with the activation of complement system.Angiotensin-converting enzyme inhibitors,such as captopril,are commonly used to treat renal I/R injury. Through the expansion of blood vessels,the blood flow is thus restored as soon as possible to reduce the ischemic time and prevent renal I/R injury.
Objective:To investigate the mechanism of renal I/R injury and its key factors,and analyze how angiotensin-converting enzyme inhibitor (captopril) have a protective effect on renal I/R injury.
Methods:In this study,I/R model was made through ligating one side renal vessel.Renal function indexes including Scr and BUN were detected through biochemical analysis;renal tissue and the corresponding protein expression were observed by pathomorphology and immunohistochemistry.At the same time,ELISA detection was used to determined inflammatory cytokines IL-6 and TNF-αin renal tissue and serum.IL-1β,TNF-αexpression and activation of MAPK signaling pathway were analyzed by RT-PCR and Western blot respectively. Turbidimetry was applied to essay serum complement.
Results:After I/R for 1 h,Scr and BUN value started to increase, and presented significantly after 2 h.Inflammatory cell infiltration was found in renal glomeruli during reperfusion for 1 h after ischemia for 30 min;while 30 min of ischemia followed by 2 h of reperfusion, deterioration of renal tubular damage with cell necrosis was observed, and a large number of inflammatory cells was infiltrated in renal interstitium.However,the levels of inflammatory cytokines IL-6 and TNF-αin serum had no significant difference between sham group and I/ R groups for different times.The contents of IL-6 and TNF-αin renal tissue treated with I/R injury for 1 h or 2 h significantly increased compared with sham group.While reperfusion for 1 h after ischemia for 30 min,the mRNA levels of inflammatory cytokines IL-6,TNF-αwere obviously up-regulated.
Western blot showed that when the renal ischemia for 30 min and without reperfusion,p38,ERK,JNK in MAPK signaling pathway were activated.With the extending of reperfusion time,p38,ERK and JNK were phosphorylated significantly(activated).At 30 min of reperfusion, MAPK phosphorylation was increased significantly,but then had no obvious change with the time of reperfusion.
In addition,we found that BUN and Scr values were decreased markedly after treatment of renal I/R injury with captopril(angiotensin inhibitors),inflammatory cell infiltration in renal glomeruli was significantly reduced,and swelling of tubular epithelial cells on the proximal and juxtamedullary regions was decreased.At the same time, the level of inflammatory cytokines IL-6 in renal tissue was reduced. However,after treatment with captopril,the JNK,ERK and P38 phosphorylation in renal tissue was still high,which had no significant difference with I/R group.
The serum complement activity(CH50) was significantly reduced during renal I/R injury,while recovered obviously after treatment with captopril.Immunocytochemistry revealed that 30 min of ischemia followed by 1 h of reperfusion,the depositions of complement activation fragment C3d were found at the basilar part of tubular epithelial cells on the proximal and juxtamedullary regions,which in amount or degree were degraded when treated with captopril.Western blot analysis indicated that activation fragment of complement C3(C3d) was observed in renal tissue after I/R injury(I/R group),and decreased after captopril treatment (CAP group).
Conclusion:Renal I/R injury can lead to increased expression of pro-inflammatory cytokines in the tissues,and can activate MAPK signaling pathway.Captopril affects the activation of complement system rather than MAPK inflammatory signaling pathway,and thus lessens I/R injury of renal tissue through inhibiting expression of some inflammatory cytokines.
引文
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