吡格列酮对STZ诱导的糖尿病大鼠肾脏和骨骼肌免疫损伤的治疗作用
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摘要
目的：糖尿病(DM)慢性并发症可累及全身各组织器官，传统的治疗方法主要为严格的控制血糖和对症处理，但效果不佳。近年来的研究发现免疫学因素在DM慢性并发症的发病过程中可能发挥重要的作用。我们近几年在临床上开展的肾活检和骨骼肌活检证实，部分2型糖尿病患者肾脏和骨骼肌有多种免疫复合物沉积。在已经完成的系列研究中，我们选用环孢菌素A(CsA)对DM大鼠短期干预(8周)，发现能明显延缓糖尿病肾脏疾病(DKD)的发生。但是当DM病程明显延长时疗效如何?我们尚需观察。近年来越来越多的研究显示，噻唑烷二酮类药物(Thiazolidinediones，TZDs)具有免疫调节作用，而TZDs是否影响DM慢性并发症时的免疫异常反应，尚未见有关研究报道。
p38丝裂原活化蛋白激酶(p38MAPK)信号转导通路是细胞信息传递的交汇点或共同通路，在应激、炎症反应、细胞凋亡、细胞内蛋白质合成与分泌、细胞分化等过程中发挥重要作用。以往的研究表明，p38MAPK的激活在DM肾脏病变、神经病变和大血管病变发病的早期阶段起到重要作用。然而，p38MAPK是否在DKD发展阶段中发挥作用尚有争议，是否参与糖尿病骨骼肌病变的发生和发展，尚未见有关研究报道。
TZDs类药物可激活脂肪细胞和肝上皮细胞p38MAPK活性，但不激活人系膜细胞p38MAPK。CsA能通过抑制钙调神经磷酸酶(CaN)和蛋白激酶C(PKC)使心肌p38MAPK活性降低。然而，TZDs和CsA是否影响DKD和糖尿病骨骼肌病变时肾皮质和骨骼肌的p38MAPK活性，尚未见有关研究报道。
本实验采用STZ诱导的DM大鼠模型，观察DKD和糖尿病骨骼肌病变时吡格列酮(PIO)、CsA对肾脏和骨骼肌免疫球蛋白异常沉积、p38MAPK活性、细胞凋亡以及炎症因子和葡萄糖转运蛋白(GLUTs)表达的影响，并确定其治疗效果，从而为临床选择药物防治DKD和糖尿病骨骼肌病变提供一定的理论依据。
方法：96只雄性SD大鼠，其中84只以静脉注射STZ的方法制造DM大鼠模型，另外12只大鼠作为正常对照组(CON组)。所有成模大鼠根据血糖水平分层后，随机分为PIO小剂量治疗组(A组，4mg／kg／d)、PIO大剂量治疗组(B组，20mg／kg／d)、PIO联合甘精胰岛素治疗组(C组，PIO 4mg／kg／d+甘精胰岛素4U／／kg／d)、CsA治疗组(D组，1mg／kg／d)、CsA联合甘精胰岛素治疗组(E组CsA1mg／kg／d+甘精胰岛素4U／／kg／d)、甘精胰岛素治疗组(F组，4U／／kg／d)、DM未治疗组(G组)。PIO配置成混悬液后予以灌胃，CsA溶于橄榄油后予以皮下注射，甘精胰岛素予以皮下注射。成模16周后处死。留取血、尿标本分别检测肾功能、胰岛素和尿微量白蛋白。光镜和电镜下观察各组大鼠肾脏和骨骼肌的病理组织学改变，通过免疫组化和免疫荧光方法检测上述器官IgG、IgA和IgM的表达。采用免疫组化方法观察DM大鼠肾脏和骨骼肌p-p38MAPK、TGFβ1、TNFα、Bax、Bcl-2、Fas、Fas-L、GLUT1和GLUT4表达水平的变化。
结果：1．G组大鼠出现明显肾小球硬化和纤维化，近端肾小管上皮细胞(PTEC)有广泛的糖原颗粒沉积、并出现局灶样或弥漫性空泡样变性。电镜观察显示肾小球毛细血管基底膜不规则增厚，系膜区增宽，上皮细胞足突融合。G组大鼠骨骼肌纤维普遍性萎缩，电镜观察显示肌丝呈灶状溶解。各PIO或CsA治疗组大鼠肾脏和骨骼肌病变均有不同程度减轻。2．G组大鼠肾皮质和骨骼肌均可见IgG、IgA、IgM异常沉积，各PIO或CsA治疗组大鼠肾皮质和骨骼肌免疫球蛋白的沉积明显减少。3．G组大鼠肾皮质p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L、GLUT1和GLUT4表达较CON组均明显增加，Bax／Bcl-2比升高。与G组相比，各PIO或CsA治疗组大鼠肾皮质以上各项指标均有不同程度降低。4．G组大鼠骨骼肌纤维p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L表达较CON组均明显增加，Bax／Bcl-2比升高，GLUT1和GLUT4表达均明显减少。与G组相比，各PIO或CsA治疗组大鼠肾皮质p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L表达量以及Bax／Bcl-2比均有不同程度降低，GLUT1表达均无变化，GLUT4表达均增加。
结论：1．STZ诱导DM大鼠的肾脏和骨骼肌均出现免疫球蛋白的异常沉积，提示在DM慢性并发症的发生和发展过程中，免疫反应可能起到了关键的作用。2．应用PIO和CsA进行免疫调节或免疫抑制治疗能有效减轻肾脏和骨骼肌病变的程度，并减少肾脏和骨骼肌中免疫球蛋白的沉积量，提示在临床上早期给予免疫调节或免疫抑制治疗可能会预防或延缓DKD和糖尿病骨骼肌病变的发生。3．在DKD的发展阶段(16周)，DM大鼠肾皮质p38MAPK信号转导通路仍被激活，同时肾皮质TGFβ1、TNF-α、促凋亡基因蛋白、GLUT1和GLUT4表达增加。以上因素相互作用，共同促进了DKD的发生和发展。4．糖尿病骨骼肌病变时，大鼠骨骼肌p38MAPK信号转导通路被激活，同时TGFβ1、TNF-α和促凋亡基因蛋白表达增加，共同促进了糖尿病骨骼肌病变的发生和发展；骨骼肌GLUT1和GLUT4表达下降导致了机体葡萄糖的利用障碍。5．PIO和CsA治疗能抑制DM大鼠肾皮质和骨骼肌p38MAPK活性，减少TGFβ1、TNF-α、促凋亡基因蛋白的表达，并改善肾脏GLUT1和GLUT4、骨骼肌GLUT4的异常表达。
The effects of pioglitazone on the autoimmune injuries to the kidneys andskeletal muscle in STZ-induced diabetic rats
Objective:The chronic complications may appear in all organs in the daibetispatients,which severely damage their health.The mechanism of these chroniccomplications still remains unclear while recent studies have implied that theabnormal immune responses may play an important role in the pathogenesis ofchronic complications of diabetes.By biopsy,we also demonstrated the deposition ofimmunological complexes and complements of various kinds on the kidneys andskeletal muscle in the most patients of T2DM.Our previous studies showed thatdiabetes kidney disease(DKD) of diabetic rats (eight weeks)could be effectivelyprevented by the administration of cyclosporine A(CsA).But we did not know howabout its effects in the rats with longer course of diabetes.Recently,more and morestudies indicate Thiazolidinediones(TZDs) showed immunoregulatory effect,butthere is no report about weather they has the regulatory effects on the abnormalautoimmunity of the chronic complications of diabetes.
p38 mitogen-activated protein kinase (MAPK) pathway plays an important rolein the processes of stress,inflammation,apoptosis,protein synthesis and secretion,and cell differentiation.p38MAPK activation is a feature of early stage of DKD,diabetic neuropathy and macrovascular disease.However,whether p38MAPKactivatin could be detected in advanced stages of DKD remains to be elucidated,andwhether p38MAPK is associated with the development of diabetic myopathy ofskeletal muscle had not been reported.
It has been shown that TZDs may activate p38MAPK in adipocytes and liverepithelial cells,but it has no effect on p38MAPK activation of human mesangial cells.p38MAPK activation may be suppressed by CsA in cardiomyocytes throughinhibitting calcineurin(CaN) and PKC.Till now,however there is still no any reporton whether p38MAPK activation could be affected by TZDs and CsA in the renalcortex and skeletal muscle during the course of DKD and diabetic myopathy of skeletal muscle.
In the current study,our investigation aimed at the abnormal deposition ofimmunoglobulins in the renal cortex and skeletal muscle of STZ-induced diabetic ratsand evaluate the protective effects of pioglitazone(PIO) and CsA against theseimmunological complexes.And the effects of pioglitazone(PIO) or CsA were studiedon the activity of p38MAPK,apoptosis,the expression of inflammatory factors andglucose transporters(GLUTs) in the diabetic rats.
Materials and methods:The DM rat models were made by intravenousinjection of STZ(45mg/kg).Then,they were randomly divided into seven groups,including small-dose PIO group (group A,4mg/kg/d),large-dose PIO group (group B,20mg/kg/d),small-dose PIO combined with glargine group (group C,PIO 4mg/kg/dand glargine 4U//kg/d),CsA group (group D,lmg/kg/d),CsA combined with glarginegroup(group E,CsA lmg/kg/d and glargine 4U//kg/d),glargine trentmentgroup(group F,glargine 4U//kg/d) and no-treatment group(group G).Another groupof normal rats(group CON) was also monitored simultaneously.Sixteen weeks later,renal function,urine albumin and serum insulin were evaluated.The pathologicalchanges were studied in kidneys and skeletal muscle by light and electron microscope.The deposition of immunoglobulins was detected on the renal cortex and skeletalmuscle by immunohistochemistry and immunofluorescence.At the same time,theexpression of p-p38MAPK,TGFβ1,TNFα,Bax,Bcl-2,Fas,Fas-L,GLUT1 andGLUT4 was detected by immunohistochemistry.
Results:1.In group G,glomerular sclerosis,fibrosis,widespread deposition ofglycogen granules in proximal tubular epithelial cells(PTEC) were showed by lightmicorscope.Irregular thicking of glomerular basement membrane,mesangialexpansion and fusion of epithelial cells foot processes were observed by electronmicroscope.Pathological changes of skeletal muscle were characterized primarily bywidespread myatrophy and dotted dissolving of myofilament.The above-mentionedchanges relieved to some extent in the groups treated with PIO or CsA.2.Comparedwith the control group,the deposition of IgG,IgA and IgM was remarkably increasedin renal cortex and skeletal muscle of group G rats.The immunoglobulins depositionon these organs was obviously decreased in PIO or CsA treatment groups than in group G.3.Compared with the control group,the expressions ofp-p38MAPK,TGFβ1,TNF-α,Bax,Fas,Fas-L,GLUT1 and GLUT4 in the renal cortexof diabetic rats were significantly increased in group G,and the ratio of Bax/Bcl-2was elevated.While all the values were obviously decreased in the groups treatedwith PIO or CsA than in group G.4.Compared with the control group,theexpressions of p-p38MAPK,TGFβ1,TNF-α,Bax,Fas and Fas-L in the skeletalmuscle were significantly increased,and the ratio of Bax/Bcl-2 was elevated,theexpression of GLUT1 and GLUT4 were decreased markedly in group G.Theexpressions of p-p38MAPK,TGFβ1,TNF-α,Bax,Fas and Fas-L were obviouslydecreased in the groups treated with PIO or CsA than in group G,and the expressionof GLUT4 was increased,but the expression of GLUT 1 had no change.
Conclusions:1.The deposition ofimmunoglobulins on renal cortex and skeletalmuscle of STZ-induced diabetic rats suggests that the autoimmune injuries happenedto those tissues and was involved in the pathogenesis of the chronic diabeticcomplications.2.Immunoregulatory or immunosuppressive treatment with PIO orCsA have demonstrated protective effects on kidney and skeletal muscle by inhibitingthe abnormal deposition of immunoglobulins on them.3.Renal cortical p38MAPKactivity was increased in diabetic rats at advanced stages of DKD,as compared withnon-diabetic rats,and the expressions of TGFβ1,TNF-α,pro-apoptotic protein,GLUT1 and GLUT4 were demonstrated in the renal cortex.All the factors interactedwith each other and promoted the development of diabetes kidney diseases.4.Thep38MAPK pathway was activated in the rats of diabetic myopathy of skeletal muscle,at the same time,the expression of TGFβ1,TNF-α,pro-apoptotic protein wereincreased.5.p38MAPK activity and the expressions of TGFβ1,TNF-αandpro-apoptotic protein could be suppressed by treatment with PIO or CsA on the renalcortex and skeletal muscle in the diabetic rats,simultaneously,abnormal expressionsof GLUT1 and GLUT4 in the kidneys and the decreased expression of GLUT4 in theskeletal muscle could be improved.
p38丝裂原活化蛋白激酶(p38MAPK)信号转导通路是细胞信息传递的交汇点或共同通路，在应激、炎症反应、细胞凋亡、细胞内蛋白质合成与分泌、细胞分化等过程中发挥重要作用。以往的研究表明，p38MAPK的激活在DM肾脏病变、神经病变和大血管病变发病的早期阶段起到重要作用。然而，p38MAPK是否在DKD发展阶段中发挥作用尚有争议，是否参与糖尿病骨骼肌病变的发生和发展，尚未见有关研究报道。
TZDs类药物可激活脂肪细胞和肝上皮细胞p38MAPK活性，但不激活人系膜细胞p38MAPK。CsA能通过抑制钙调神经磷酸酶(CaN)和蛋白激酶C(PKC)使心肌p38MAPK活性降低。然而，TZDs和CsA是否影响DKD和糖尿病骨骼肌病变时肾皮质和骨骼肌的p38MAPK活性，尚未见有关研究报道。
本实验采用STZ诱导的DM大鼠模型，观察DKD和糖尿病骨骼肌病变时吡格列酮(PIO)、CsA对肾脏和骨骼肌免疫球蛋白异常沉积、p38MAPK活性、细胞凋亡以及炎症因子和葡萄糖转运蛋白(GLUTs)表达的影响，并确定其治疗效果，从而为临床选择药物防治DKD和糖尿病骨骼肌病变提供一定的理论依据。
方法：96只雄性SD大鼠，其中84只以静脉注射STZ的方法制造DM大鼠模型，另外12只大鼠作为正常对照组(CON组)。所有成模大鼠根据血糖水平分层后，随机分为PIO小剂量治疗组(A组，4mg／kg／d)、PIO大剂量治疗组(B组，20mg／kg／d)、PIO联合甘精胰岛素治疗组(C组，PIO 4mg／kg／d+甘精胰岛素4U／／kg／d)、CsA治疗组(D组，1mg／kg／d)、CsA联合甘精胰岛素治疗组(E组CsA1mg／kg／d+甘精胰岛素4U／／kg／d)、甘精胰岛素治疗组(F组，4U／／kg／d)、DM未治疗组(G组)。PIO配置成混悬液后予以灌胃，CsA溶于橄榄油后予以皮下注射，甘精胰岛素予以皮下注射。成模16周后处死。留取血、尿标本分别检测肾功能、胰岛素和尿微量白蛋白。光镜和电镜下观察各组大鼠肾脏和骨骼肌的病理组织学改变，通过免疫组化和免疫荧光方法检测上述器官IgG、IgA和IgM的表达。采用免疫组化方法观察DM大鼠肾脏和骨骼肌p-p38MAPK、TGFβ1、TNFα、Bax、Bcl-2、Fas、Fas-L、GLUT1和GLUT4表达水平的变化。
结果：1．G组大鼠出现明显肾小球硬化和纤维化，近端肾小管上皮细胞(PTEC)有广泛的糖原颗粒沉积、并出现局灶样或弥漫性空泡样变性。电镜观察显示肾小球毛细血管基底膜不规则增厚，系膜区增宽，上皮细胞足突融合。G组大鼠骨骼肌纤维普遍性萎缩，电镜观察显示肌丝呈灶状溶解。各PIO或CsA治疗组大鼠肾脏和骨骼肌病变均有不同程度减轻。2．G组大鼠肾皮质和骨骼肌均可见IgG、IgA、IgM异常沉积，各PIO或CsA治疗组大鼠肾皮质和骨骼肌免疫球蛋白的沉积明显减少。3．G组大鼠肾皮质p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L、GLUT1和GLUT4表达较CON组均明显增加，Bax／Bcl-2比升高。与G组相比，各PIO或CsA治疗组大鼠肾皮质以上各项指标均有不同程度降低。4．G组大鼠骨骼肌纤维p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L表达较CON组均明显增加，Bax／Bcl-2比升高，GLUT1和GLUT4表达均明显减少。与G组相比，各PIO或CsA治疗组大鼠肾皮质p-p38MAPK、TGFβ1、TNF-α、Bax、Fas、Fas-L表达量以及Bax／Bcl-2比均有不同程度降低，GLUT1表达均无变化，GLUT4表达均增加。
结论：1．STZ诱导DM大鼠的肾脏和骨骼肌均出现免疫球蛋白的异常沉积，提示在DM慢性并发症的发生和发展过程中，免疫反应可能起到了关键的作用。2．应用PIO和CsA进行免疫调节或免疫抑制治疗能有效减轻肾脏和骨骼肌病变的程度，并减少肾脏和骨骼肌中免疫球蛋白的沉积量，提示在临床上早期给予免疫调节或免疫抑制治疗可能会预防或延缓DKD和糖尿病骨骼肌病变的发生。3．在DKD的发展阶段(16周)，DM大鼠肾皮质p38MAPK信号转导通路仍被激活，同时肾皮质TGFβ1、TNF-α、促凋亡基因蛋白、GLUT1和GLUT4表达增加。以上因素相互作用，共同促进了DKD的发生和发展。4．糖尿病骨骼肌病变时，大鼠骨骼肌p38MAPK信号转导通路被激活，同时TGFβ1、TNF-α和促凋亡基因蛋白表达增加，共同促进了糖尿病骨骼肌病变的发生和发展；骨骼肌GLUT1和GLUT4表达下降导致了机体葡萄糖的利用障碍。5．PIO和CsA治疗能抑制DM大鼠肾皮质和骨骼肌p38MAPK活性，减少TGFβ1、TNF-α、促凋亡基因蛋白的表达，并改善肾脏GLUT1和GLUT4、骨骼肌GLUT4的异常表达。
The effects of pioglitazone on the autoimmune injuries to the kidneys andskeletal muscle in STZ-induced diabetic rats
Objective:The chronic complications may appear in all organs in the daibetispatients,which severely damage their health.The mechanism of these chroniccomplications still remains unclear while recent studies have implied that theabnormal immune responses may play an important role in the pathogenesis ofchronic complications of diabetes.By biopsy,we also demonstrated the deposition ofimmunological complexes and complements of various kinds on the kidneys andskeletal muscle in the most patients of T2DM.Our previous studies showed thatdiabetes kidney disease(DKD) of diabetic rats (eight weeks)could be effectivelyprevented by the administration of cyclosporine A(CsA).But we did not know howabout its effects in the rats with longer course of diabetes.Recently,more and morestudies indicate Thiazolidinediones(TZDs) showed immunoregulatory effect,butthere is no report about weather they has the regulatory effects on the abnormalautoimmunity of the chronic complications of diabetes.
p38 mitogen-activated protein kinase (MAPK) pathway plays an important rolein the processes of stress,inflammation,apoptosis,protein synthesis and secretion,and cell differentiation.p38MAPK activation is a feature of early stage of DKD,diabetic neuropathy and macrovascular disease.However,whether p38MAPKactivatin could be detected in advanced stages of DKD remains to be elucidated,andwhether p38MAPK is associated with the development of diabetic myopathy ofskeletal muscle had not been reported.
It has been shown that TZDs may activate p38MAPK in adipocytes and liverepithelial cells,but it has no effect on p38MAPK activation of human mesangial cells.p38MAPK activation may be suppressed by CsA in cardiomyocytes throughinhibitting calcineurin(CaN) and PKC.Till now,however there is still no any reporton whether p38MAPK activation could be affected by TZDs and CsA in the renalcortex and skeletal muscle during the course of DKD and diabetic myopathy of skeletal muscle.
In the current study,our investigation aimed at the abnormal deposition ofimmunoglobulins in the renal cortex and skeletal muscle of STZ-induced diabetic ratsand evaluate the protective effects of pioglitazone(PIO) and CsA against theseimmunological complexes.And the effects of pioglitazone(PIO) or CsA were studiedon the activity of p38MAPK,apoptosis,the expression of inflammatory factors andglucose transporters(GLUTs) in the diabetic rats.
Materials and methods:The DM rat models were made by intravenousinjection of STZ(45mg/kg).Then,they were randomly divided into seven groups,including small-dose PIO group (group A,4mg/kg/d),large-dose PIO group (group B,20mg/kg/d),small-dose PIO combined with glargine group (group C,PIO 4mg/kg/dand glargine 4U//kg/d),CsA group (group D,lmg/kg/d),CsA combined with glarginegroup(group E,CsA lmg/kg/d and glargine 4U//kg/d),glargine trentmentgroup(group F,glargine 4U//kg/d) and no-treatment group(group G).Another groupof normal rats(group CON) was also monitored simultaneously.Sixteen weeks later,renal function,urine albumin and serum insulin were evaluated.The pathologicalchanges were studied in kidneys and skeletal muscle by light and electron microscope.The deposition of immunoglobulins was detected on the renal cortex and skeletalmuscle by immunohistochemistry and immunofluorescence.At the same time,theexpression of p-p38MAPK,TGFβ1,TNFα,Bax,Bcl-2,Fas,Fas-L,GLUT1 andGLUT4 was detected by immunohistochemistry.
Results:1.In group G,glomerular sclerosis,fibrosis,widespread deposition ofglycogen granules in proximal tubular epithelial cells(PTEC) were showed by lightmicorscope.Irregular thicking of glomerular basement membrane,mesangialexpansion and fusion of epithelial cells foot processes were observed by electronmicroscope.Pathological changes of skeletal muscle were characterized primarily bywidespread myatrophy and dotted dissolving of myofilament.The above-mentionedchanges relieved to some extent in the groups treated with PIO or CsA.2.Comparedwith the control group,the deposition of IgG,IgA and IgM was remarkably increasedin renal cortex and skeletal muscle of group G rats.The immunoglobulins depositionon these organs was obviously decreased in PIO or CsA treatment groups than in group G.3.Compared with the control group,the expressions ofp-p38MAPK,TGFβ1,TNF-α,Bax,Fas,Fas-L,GLUT1 and GLUT4 in the renal cortexof diabetic rats were significantly increased in group G,and the ratio of Bax/Bcl-2was elevated.While all the values were obviously decreased in the groups treatedwith PIO or CsA than in group G.4.Compared with the control group,theexpressions of p-p38MAPK,TGFβ1,TNF-α,Bax,Fas and Fas-L in the skeletalmuscle were significantly increased,and the ratio of Bax/Bcl-2 was elevated,theexpression of GLUT1 and GLUT4 were decreased markedly in group G.Theexpressions of p-p38MAPK,TGFβ1,TNF-α,Bax,Fas and Fas-L were obviouslydecreased in the groups treated with PIO or CsA than in group G,and the expressionof GLUT4 was increased,but the expression of GLUT 1 had no change.
Conclusions:1.The deposition ofimmunoglobulins on renal cortex and skeletalmuscle of STZ-induced diabetic rats suggests that the autoimmune injuries happenedto those tissues and was involved in the pathogenesis of the chronic diabeticcomplications.2.Immunoregulatory or immunosuppressive treatment with PIO orCsA have demonstrated protective effects on kidney and skeletal muscle by inhibitingthe abnormal deposition of immunoglobulins on them.3.Renal cortical p38MAPKactivity was increased in diabetic rats at advanced stages of DKD,as compared withnon-diabetic rats,and the expressions of TGFβ1,TNF-α,pro-apoptotic protein,GLUT1 and GLUT4 were demonstrated in the renal cortex.All the factors interactedwith each other and promoted the development of diabetes kidney diseases.4.Thep38MAPK pathway was activated in the rats of diabetic myopathy of skeletal muscle,at the same time,the expression of TGFβ1,TNF-α,pro-apoptotic protein wereincreased.5.p38MAPK activity and the expressions of TGFβ1,TNF-αandpro-apoptotic protein could be suppressed by treatment with PIO or CsA on the renalcortex and skeletal muscle in the diabetic rats,simultaneously,abnormal expressionsof GLUT1 and GLUT4 in the kidneys and the decreased expression of GLUT4 in theskeletal muscle could be improved.
引文
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