右美托咪啶对肾脏缺血再灌注致肾及肺损伤的保护作用和机制研究
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摘要
肾脏缺血再灌注(IR)导致的急性肾损伤(AKI)或急性肾衰(ARF)是围手术期常见并发症之一,常常造成住院时间延长,诊治费用增加,死亡率增高。近期调查显示,尽管透析技术和治疗方法在过去二十年里改进不少,但与AKI相关的发病率和死亡率无明显下降。AKI很少独立出现,往往同时伴随肾外器官的病理性损伤和功能障碍。其中,由于肺脏拥有巨大的毛细血管网络,对于肾脏IR引起的血循环促炎调节因子更为敏感,使之更容易发生急性肺损伤(ALI)。AKI合并ALI时,死亡率可高达80%。然而,当前仍缺乏一种方法能有效防阻肾脏IR导致的肾和肺损伤。因此,进一步探寻有效方法降低肾脏缺血再灌注损伤(IRI)及其导致的ALI具有重要意义。
近年研究证实,肾小管上皮细胞凋亡以及由Toll样受体4(TLR4)介导的免疫炎症反应是导致肾脏IRI的重要机制。通过激活细胞抗凋亡信号级联反应,减少肾小管细胞凋亡;或者通过阻断TLR4信号通路,降低炎症反应,已成为减轻肾脏IRI一种思路与策略。
右美托咪啶(Dexmedetomidine,Dex)是一种新型高选择性α2肾上腺素能受体(α2AR)激动剂,具有镇静、镇痛、稳定血流动力学和利尿的作用,目前主要应用于ICU镇静和临床麻醉。近来实验发现,Dex还可激活神经系统相关保护信号通路,减少神经细胞凋亡;心机缺血时能减少梗阻面积,改善围手术期心功能;在脓毒症镇静中还可减少促炎细胞因子,降低炎症反应,提高生存率。这些研究反映了Dex具有细胞保护和抗炎的作用。据此我们推测,肾脏IRI时Dex可提供肾和肺的双重保护,改善生存率。本实验目的就是验证肾脏IR后Dex的肾肺保护效应,并探索其相关的机制。
研究内容:
1.C57BL/6J小鼠双肾IR前或后应用Dex,通过HE染色检测肾脏组织病理学变化,TUNEL染色检测肾实质细胞凋亡水平,血生化测定肾功能,免疫组化和Western blot检测肾脏TLR4蛋白表达,以及ILISA测定血浆高迁移率族蛋白1(HMGB1)水平。左肾脏切除,右肾IR,评估Dex对ARF C57BL/6J小鼠存活率的影响。
2.传代培养人近曲肾小管上皮细胞(HK2),用MTT法检测Dex对OGD诱导HK2损伤的影响。并应用Wester blot检测Dex对HK2中总Akt(Akt蛋白表达)以及磷酸化Akt(pAkt蛋白表达)的作用。
3. C57BL/6J小鼠双肾IR前或后应用Dex,通过HE染色检测肺脏组织病理学变化,测定肺湿干比重,血生化检测肺髓过氧化物酶(MPO),并应用RT-PCR和Real-time PCR测定肺脏ICAM-1和TNF-αmRNA表达。
结果: 1.肾脏缺血25min再灌注24h后,肾组织病理损伤明显,细胞凋亡增多,血浆肌酐(Cr)和尿素氮(Ur)显著升高。IR前或后应用Dex25μg/kg,组织病理损伤降低53%和38%;细胞凋亡减少72%和58%;血清Cr和Ur明显降低。α2AR拮抗剂阿替美唑(Atipamezole,Atip)250μg/kg可完全抑制上述Dex的肾保护效应。
2.肾脏缺血25min再灌注24h后,肾脏TLR4蛋白表达和血浆HMGB1浓度显著升高,缺血前应用Dex 25μg/kg,显著下调TLR4表达和HMGB1浓度。应用Atip 250μg/kg后,Dex下调TLR4蛋白表达以及血清HMGB1水平的作用消失。
3.生存率实验显示,IR前或后经Dex处理的动物生存率分别为70%和60%。无处理或联合应用Atip与Dex,3天后死亡率约为65%,所有动物存活时间未超过5天。
4.经OGD处理的HK2,随时间延长,细胞死亡逐渐增多。OGD处理180min时,细胞死亡达到60%。Dex 0.001、0.01、0.1nM预处理HK2后,其存活率呈剂量相关性增加。经Dex 0.1nM处理HK2,其存活率达94%。Atip 1nM完全抑制Dex对HK2的保护效应。
5.HK2经0.1nM Dex处理5、10、20、30、45 min,各时间点pAkt蛋白表达均升高,20min时达到峰值,之后逐渐降低,而总Akt表达未发生变化。Atip1nM不能完全抑制Dex上调pAkt表达的效应。Dex上调pAkt蛋白表达的作用可被PI3K抑制剂LY294002(50μM)完全抑制,而MAPK抑制剂PD98059(50μM)无此效应。
6.双肾缺血45min,再灌注6h后,肺脏间质固有层解体并伴出血,肺间质细胞增多,肺泡腔缩窄甚至消失;肺湿干比重升高3.5倍;MPO活性增加1倍;ICAM-1和TNF-αmRNA表达分别升高7倍和10倍。IR前或后应用Dex,肺湿干比重下降约三分之一,MPO活性分别降低58%和16%,并且抑制ICAM-1和TNF-αmRNA过表达,肺组织病理损伤明显减轻。Atip可抑制Dex下调肺湿干比重以及MPO活性的作用,但不能抑制其下调ICAM-1和TNF-αmRNA过表达的效应。
结论:
1.右美托咪啶对C57BL/6J小鼠肾脏IRI具有保护性作用。
2.右美托咪啶通过激动α2AR,抑制肾脏细胞凋亡,下调TLR4蛋白表达以及血清HMGB1的水平,是其肾保护的主要机制。
3.右美托咪啶可减轻OGD诱导的HK2损伤。通过α2AR依赖和非依赖途径,激活PI3K-Akt信号通路可能是其主要机制。
4.右美托咪啶可减轻C57BL/6J小鼠肾脏IR所致的肺损伤。
5.通过激动α2AR依赖和非依赖信号途径,减轻肺部炎症反应,是右美托咪啶保护肾脏IR所致肺损伤的机制。
Acute kidney injury(AKI) or Acute renal failure(ARF) induced by renal ischemia reperfusion(IR) is a common complication during perioperation, which is usually associated with increased duration of hospital stay, healthcare cost and mortality. Recent investigations demonstrated that despite improvements in dialysis technology and advances in supportive care, the morbidity and mortality associated with AKI has remained unchanged over the past two decades. AKI rarely occurs in isolation and is usually accomplicated by extrarenal organ pathologic injury and dysfunction. The lung, as an organ with large microcapillary network, is highly susceptible to injury caused by circulating pro-inflammatory mediators from kidney inflicted with ischemia reperfusion. The mortality rate of combined ARF and acute lung injury (ALI) could be up to 80%. Unfortunately, currently more effective methods to reduce renal ischemia reperfusion injury(IRI) and its induced ALI are still deficiency and anticipated. Therefore, it is significantly and necessarily to explore more better curative methods to reduce them.
Recently, some studies have proved that apoptosis in tubular epithelium and immune inflammatory reaction mediated via TLR4 are the critical mechanisms leading to renal IRI. Trigger of anti-apoptosis signal cascade to reduce epithelia apoptosis or inhibition of TLR4 signaling to relieve inflammation are becoming a novel strategy to ameliorate renal IRI
Dexmedetomeding(Dex), applied in ICU sedation and clinical anesthesia currently, is a highly potentα2 adrenergic agonist with sedative, analgesic, hemodynamic stabilizing and diuretic effects. Some recent experiments demonstrated that Dex was able to activate protective signaling pathway to reduce neural cell apoptosis, it also could reduce myocardial infarct size and improve perioperative cardiac function as well as exert anti-inflammatory effects and improve survival rate by decreasing pro-inflammatory mediators during sedation for sepsis. Therefore, it may be naturally speculated that Dex can probably provide kidney and lung protection to improve mortality following renal IRI. The purpose of this research is to verify the hypothesis and further explore related mechanisms.
Methods
1. C57BL/6J mice were subjected to bilateral renal IR with or without Dex treatment and then followed by HE staining for renal histopathological assessment, TUNEL staining for tubular cell apoptosis evaluation, biochemical analysis for renal function, immuohistochemistry and Western blot for expression of kidney TLR4, ILISA for plasma HMGB1 level. The mortality was assessed after right renal IR and left nephrectomy with or without Dex treatment.
2. HK2 were subcultured and the effects of Dex on HK2 injury induced by OGD were evaluated by MTT assay. Protein expressions of total Akt and phosphorylation Akt(pAkt) in HK2 with Dex treatment were determined by Western blot.
3. Lungs were obtained from C57BL/6J mice subjected to bilateral renal IR with or without Dex treatment and then followed by HE staining for histopathological assessment, lung wet/dry ratio evaluation, biochemical analysis for MPO activity, RT-PCR and FQ-PCR for mRNA expression of ICAM-1and TNF-α.
Results
1. Increased kidney histopathological injury, tubular cell apoptosis and plasma creatinin and urea level were detected after renal ischemia 25 min and reperfuse 24 h. Pre- or post-treatment with Dex 25μg/kg resulted in 53% and 38% reduction in damage, 72% and 58% reduction in cell apoptosis as well as significant decrease in plasma creatinin and urea level.α2 adrenoceptor antagonist Atipamezole(Atip) 250μg/kg abrogated renal protective effects of Dex.
2. Expression of TLR4 proteins and plasma HMGB1 level were increased after renal ischemia 25 min and reperfuse 24 h. Pre-treatment with Dex 25μg/kg downregulated them. Atip 250μg/kg reversed the downregulated effects of Dex on TLR4 and HMGB1.
3. Long-term survival was noted in 70% and 60% of animal treated with Dex before and after renal IRI within 7 day. By contrast, animal not treated with Dex or receiving Atip combined Dex fared much worse. Within 3 day, 65% of these animals were dead and no animal survived beyond 5 day.
4. HK2 viability analysis using MTT assay showed a time-dependent induction of injury with marked cell death(60% reduction in viability) occurring after 180-min OGD. Incubating HK2 with Dex(0.001, 0.01 and 0.1 nM) before OGD exposure dose- dependently inhibited injury. Treatment with 0.1 nM Dex increased cell viability to 94%. The cytoprotective effect of Dex was abolished by co-treatment with Atip 1 nM.
5. HK2 incubated with media containing 0.1 nM Dex for 5, 10, 20, 30, 45 min. pAkt was increased at all time points and peaked after 20 min whereas total Akt were not altered. Atip 1 nM reduced but not completely abolish Dex induced upregulation of pAkt. PI3-Akt inhibitor LY294002(50μM) rather than MAPK inhibitor PD98059 (50μM) completely abolished Dex-induced activation of Akt.
6. Bilateral renal ischemia 45 min followed by 6 h reperfusion induced histopathological injury, 3.5 fold increasing of lung wet/dry ratio, 1 fold increasing of MPO activity, 7 and 10 fold upregulation of mRNA expression of ICAM-1 and TNF-αin lung. Pre- or post-treatment with Dex resulted in about one third decreasing of lung wet/dry ratio, 58% and 16% decline of MPO activity, moreover significantly inhibited mRNA overexpression of CAM-1 and TNF-αand ameliorated lung injury. Atip abrogated the downregulated effects of Dex on wet/dry ration and MPO activity but failed to reverse the downregulated effects of Dex on ICAM-1 and TNF-αmRNA.
Conclusions
1. Dex provides renoprotection against ischemia-reperfusion injury in C57BL/6J mice.
2. It is main renoprotective mechanism that Dex inhibits cell apoptosis and downregulates protein expression of TLR4 and plasma level of HMGB1 via activatingα2 adrenoceptor.
3. Dex is able to reduce HK2 injury induced by OGD and the activation of PI3K-Akt signaling viaα2 adrenoceptor dependent and independent pathway is probably the main mechanism.
4. Dex attenuates remote lung injury induced by renal ischemia-reperfusion in C57BL/6J mice.
5. The mechanism of Dex’pulmonary protection is that lung inflammation may be ameliorated via triggeringα2 adrenoceptor dependent and independent signal pathway.
近年研究证实,肾小管上皮细胞凋亡以及由Toll样受体4(TLR4)介导的免疫炎症反应是导致肾脏IRI的重要机制。通过激活细胞抗凋亡信号级联反应,减少肾小管细胞凋亡;或者通过阻断TLR4信号通路,降低炎症反应,已成为减轻肾脏IRI一种思路与策略。
右美托咪啶(Dexmedetomidine,Dex)是一种新型高选择性α2肾上腺素能受体(α2AR)激动剂,具有镇静、镇痛、稳定血流动力学和利尿的作用,目前主要应用于ICU镇静和临床麻醉。近来实验发现,Dex还可激活神经系统相关保护信号通路,减少神经细胞凋亡;心机缺血时能减少梗阻面积,改善围手术期心功能;在脓毒症镇静中还可减少促炎细胞因子,降低炎症反应,提高生存率。这些研究反映了Dex具有细胞保护和抗炎的作用。据此我们推测,肾脏IRI时Dex可提供肾和肺的双重保护,改善生存率。本实验目的就是验证肾脏IR后Dex的肾肺保护效应,并探索其相关的机制。
研究内容:
1.C57BL/6J小鼠双肾IR前或后应用Dex,通过HE染色检测肾脏组织病理学变化,TUNEL染色检测肾实质细胞凋亡水平,血生化测定肾功能,免疫组化和Western blot检测肾脏TLR4蛋白表达,以及ILISA测定血浆高迁移率族蛋白1(HMGB1)水平。左肾脏切除,右肾IR,评估Dex对ARF C57BL/6J小鼠存活率的影响。
2.传代培养人近曲肾小管上皮细胞(HK2),用MTT法检测Dex对OGD诱导HK2损伤的影响。并应用Wester blot检测Dex对HK2中总Akt(Akt蛋白表达)以及磷酸化Akt(pAkt蛋白表达)的作用。
3. C57BL/6J小鼠双肾IR前或后应用Dex,通过HE染色检测肺脏组织病理学变化,测定肺湿干比重,血生化检测肺髓过氧化物酶(MPO),并应用RT-PCR和Real-time PCR测定肺脏ICAM-1和TNF-αmRNA表达。
结果: 1.肾脏缺血25min再灌注24h后,肾组织病理损伤明显,细胞凋亡增多,血浆肌酐(Cr)和尿素氮(Ur)显著升高。IR前或后应用Dex25μg/kg,组织病理损伤降低53%和38%;细胞凋亡减少72%和58%;血清Cr和Ur明显降低。α2AR拮抗剂阿替美唑(Atipamezole,Atip)250μg/kg可完全抑制上述Dex的肾保护效应。
2.肾脏缺血25min再灌注24h后,肾脏TLR4蛋白表达和血浆HMGB1浓度显著升高,缺血前应用Dex 25μg/kg,显著下调TLR4表达和HMGB1浓度。应用Atip 250μg/kg后,Dex下调TLR4蛋白表达以及血清HMGB1水平的作用消失。
3.生存率实验显示,IR前或后经Dex处理的动物生存率分别为70%和60%。无处理或联合应用Atip与Dex,3天后死亡率约为65%,所有动物存活时间未超过5天。
4.经OGD处理的HK2,随时间延长,细胞死亡逐渐增多。OGD处理180min时,细胞死亡达到60%。Dex 0.001、0.01、0.1nM预处理HK2后,其存活率呈剂量相关性增加。经Dex 0.1nM处理HK2,其存活率达94%。Atip 1nM完全抑制Dex对HK2的保护效应。
5.HK2经0.1nM Dex处理5、10、20、30、45 min,各时间点pAkt蛋白表达均升高,20min时达到峰值,之后逐渐降低,而总Akt表达未发生变化。Atip1nM不能完全抑制Dex上调pAkt表达的效应。Dex上调pAkt蛋白表达的作用可被PI3K抑制剂LY294002(50μM)完全抑制,而MAPK抑制剂PD98059(50μM)无此效应。
6.双肾缺血45min,再灌注6h后,肺脏间质固有层解体并伴出血,肺间质细胞增多,肺泡腔缩窄甚至消失;肺湿干比重升高3.5倍;MPO活性增加1倍;ICAM-1和TNF-αmRNA表达分别升高7倍和10倍。IR前或后应用Dex,肺湿干比重下降约三分之一,MPO活性分别降低58%和16%,并且抑制ICAM-1和TNF-αmRNA过表达,肺组织病理损伤明显减轻。Atip可抑制Dex下调肺湿干比重以及MPO活性的作用,但不能抑制其下调ICAM-1和TNF-αmRNA过表达的效应。
结论:
1.右美托咪啶对C57BL/6J小鼠肾脏IRI具有保护性作用。
2.右美托咪啶通过激动α2AR,抑制肾脏细胞凋亡,下调TLR4蛋白表达以及血清HMGB1的水平,是其肾保护的主要机制。
3.右美托咪啶可减轻OGD诱导的HK2损伤。通过α2AR依赖和非依赖途径,激活PI3K-Akt信号通路可能是其主要机制。
4.右美托咪啶可减轻C57BL/6J小鼠肾脏IR所致的肺损伤。
5.通过激动α2AR依赖和非依赖信号途径,减轻肺部炎症反应,是右美托咪啶保护肾脏IR所致肺损伤的机制。
Acute kidney injury(AKI) or Acute renal failure(ARF) induced by renal ischemia reperfusion(IR) is a common complication during perioperation, which is usually associated with increased duration of hospital stay, healthcare cost and mortality. Recent investigations demonstrated that despite improvements in dialysis technology and advances in supportive care, the morbidity and mortality associated with AKI has remained unchanged over the past two decades. AKI rarely occurs in isolation and is usually accomplicated by extrarenal organ pathologic injury and dysfunction. The lung, as an organ with large microcapillary network, is highly susceptible to injury caused by circulating pro-inflammatory mediators from kidney inflicted with ischemia reperfusion. The mortality rate of combined ARF and acute lung injury (ALI) could be up to 80%. Unfortunately, currently more effective methods to reduce renal ischemia reperfusion injury(IRI) and its induced ALI are still deficiency and anticipated. Therefore, it is significantly and necessarily to explore more better curative methods to reduce them.
Recently, some studies have proved that apoptosis in tubular epithelium and immune inflammatory reaction mediated via TLR4 are the critical mechanisms leading to renal IRI. Trigger of anti-apoptosis signal cascade to reduce epithelia apoptosis or inhibition of TLR4 signaling to relieve inflammation are becoming a novel strategy to ameliorate renal IRI
Dexmedetomeding(Dex), applied in ICU sedation and clinical anesthesia currently, is a highly potentα2 adrenergic agonist with sedative, analgesic, hemodynamic stabilizing and diuretic effects. Some recent experiments demonstrated that Dex was able to activate protective signaling pathway to reduce neural cell apoptosis, it also could reduce myocardial infarct size and improve perioperative cardiac function as well as exert anti-inflammatory effects and improve survival rate by decreasing pro-inflammatory mediators during sedation for sepsis. Therefore, it may be naturally speculated that Dex can probably provide kidney and lung protection to improve mortality following renal IRI. The purpose of this research is to verify the hypothesis and further explore related mechanisms.
Methods
1. C57BL/6J mice were subjected to bilateral renal IR with or without Dex treatment and then followed by HE staining for renal histopathological assessment, TUNEL staining for tubular cell apoptosis evaluation, biochemical analysis for renal function, immuohistochemistry and Western blot for expression of kidney TLR4, ILISA for plasma HMGB1 level. The mortality was assessed after right renal IR and left nephrectomy with or without Dex treatment.
2. HK2 were subcultured and the effects of Dex on HK2 injury induced by OGD were evaluated by MTT assay. Protein expressions of total Akt and phosphorylation Akt(pAkt) in HK2 with Dex treatment were determined by Western blot.
3. Lungs were obtained from C57BL/6J mice subjected to bilateral renal IR with or without Dex treatment and then followed by HE staining for histopathological assessment, lung wet/dry ratio evaluation, biochemical analysis for MPO activity, RT-PCR and FQ-PCR for mRNA expression of ICAM-1and TNF-α.
Results
1. Increased kidney histopathological injury, tubular cell apoptosis and plasma creatinin and urea level were detected after renal ischemia 25 min and reperfuse 24 h. Pre- or post-treatment with Dex 25μg/kg resulted in 53% and 38% reduction in damage, 72% and 58% reduction in cell apoptosis as well as significant decrease in plasma creatinin and urea level.α2 adrenoceptor antagonist Atipamezole(Atip) 250μg/kg abrogated renal protective effects of Dex.
2. Expression of TLR4 proteins and plasma HMGB1 level were increased after renal ischemia 25 min and reperfuse 24 h. Pre-treatment with Dex 25μg/kg downregulated them. Atip 250μg/kg reversed the downregulated effects of Dex on TLR4 and HMGB1.
3. Long-term survival was noted in 70% and 60% of animal treated with Dex before and after renal IRI within 7 day. By contrast, animal not treated with Dex or receiving Atip combined Dex fared much worse. Within 3 day, 65% of these animals were dead and no animal survived beyond 5 day.
4. HK2 viability analysis using MTT assay showed a time-dependent induction of injury with marked cell death(60% reduction in viability) occurring after 180-min OGD. Incubating HK2 with Dex(0.001, 0.01 and 0.1 nM) before OGD exposure dose- dependently inhibited injury. Treatment with 0.1 nM Dex increased cell viability to 94%. The cytoprotective effect of Dex was abolished by co-treatment with Atip 1 nM.
5. HK2 incubated with media containing 0.1 nM Dex for 5, 10, 20, 30, 45 min. pAkt was increased at all time points and peaked after 20 min whereas total Akt were not altered. Atip 1 nM reduced but not completely abolish Dex induced upregulation of pAkt. PI3-Akt inhibitor LY294002(50μM) rather than MAPK inhibitor PD98059 (50μM) completely abolished Dex-induced activation of Akt.
6. Bilateral renal ischemia 45 min followed by 6 h reperfusion induced histopathological injury, 3.5 fold increasing of lung wet/dry ratio, 1 fold increasing of MPO activity, 7 and 10 fold upregulation of mRNA expression of ICAM-1 and TNF-αin lung. Pre- or post-treatment with Dex resulted in about one third decreasing of lung wet/dry ratio, 58% and 16% decline of MPO activity, moreover significantly inhibited mRNA overexpression of CAM-1 and TNF-αand ameliorated lung injury. Atip abrogated the downregulated effects of Dex on wet/dry ration and MPO activity but failed to reverse the downregulated effects of Dex on ICAM-1 and TNF-αmRNA.
Conclusions
1. Dex provides renoprotection against ischemia-reperfusion injury in C57BL/6J mice.
2. It is main renoprotective mechanism that Dex inhibits cell apoptosis and downregulates protein expression of TLR4 and plasma level of HMGB1 via activatingα2 adrenoceptor.
3. Dex is able to reduce HK2 injury induced by OGD and the activation of PI3K-Akt signaling viaα2 adrenoceptor dependent and independent pathway is probably the main mechanism.
4. Dex attenuates remote lung injury induced by renal ischemia-reperfusion in C57BL/6J mice.
5. The mechanism of Dex’pulmonary protection is that lung inflammation may be ameliorated via triggeringα2 adrenoceptor dependent and independent signal pathway.
引文
1. Borthwick E, Ferguson A. Perioperative acute kidney injury: risk factors, recognition, management, and outcomes. BMJ. 2010; 341:c3365.
2. Kheterpal S, Tremper KK, Heung M, Rosenberg AL, Englesbe M, Shanks AM, Campbell DA Jr. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Anesthesiology. 2009; 110(3):505-15.
3. Loef BG, Epema AH, Smilde TD, Henning RH, Ebels T, Navis G, Stegeman CA. Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival. J Am Soc Nephrol. 2005; 16(1):195-200.
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