替米沙坦对糖尿病大鼠血清MCP-1致肾脏微血管病变影响的实验研究
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摘要
目的：单核细胞趋化蛋白-1(monocyte chemoattractant protein-1, MCP-1)是调节单核/巨噬细胞迁移与渗透的最重要的炎性趋化因子,可引起血管内皮损伤,诱导血管平滑肌细胞增殖和迁移,加重动脉粥样硬化病变。长期高血糖形成的高级糖基化终末产物及糖尿病状态时一氧化氮合成减少或活性下降均可使MCP-1的表达增加。本实验以糖尿病OLETF (otsuka long-evans tokushima fatty)伴有肾病大鼠及其同系对照组LETO (Long-Evans Tokushima)大鼠为研究对象,探讨RAS阻断剂替米沙坦对糖尿病大鼠血清MCP-1及相应肾脏微血管病变的影响。
方法：由日本大冢研究所提供的OLETF (Otsuka Long-Evans Tokushima Fatty)雄性4周龄大鼠24只及正常无糖尿病对照组LETO (Long-Evans Tokushima)雄性4周龄大鼠10只,体质量均为150-200g。OLETF雄性大鼠予以高脂饮食喂养和正常对照组LETO大鼠予以普通饲料喂养,根据对大鼠的不同处理方法分为四组：OLETF模型组大鼠随机分为三组,即替米沙坦组(MT),二甲双胍组(MET),未做干预的模型组(MX)及无干预的正常无糖尿病对照组(NC)。干预42周后,全部动物禁食12小时后处死离心分离血清及肾周组织。检测血清MCP-1、FFA、FINS、FBG、TC、TG、LDL、HDL、BUN、Cr及24h尿蛋白水平,用透射电子显微镜观察大鼠肾小球滤过膜的超微结构；采用免疫组化法检测肾血管内皮组织MCP-1的表达水平；胰岛素抵抗指数(HOMA-IR)=(FINS×FBG)÷22.5;比较各组之间以上各指标的差异,并比较MCP-1与FFA、FINS、FBG、TC、TG、LDL、HDL等生化指标之间的相关性；所有结果均采用SPSS15.0软件分析处理。
结果：1组间大鼠血清MCP-1水平比较：与正常对照组[(30.91±4.42)pg/ml]比较,模型组大鼠血清MCP-1水平[(44.92±7.21)pg/ml]增高(P<0.05)；与药物干预替米沙坦组[(32.70±6.71)pg/ml]、二甲双胍组[(33.33±4.47)pg/ml]比较,模型组大鼠血清MCP-1水平[(44.92±7.21)pg/ml]增高(P<0.05)。
2相关性分析：直线相关分析显示血清MCP-1水平与FFA、TC、TG、LDL、FINS、HOMA-IR指数呈正相关(r、P分别为0.686,0.001；0.537,0.001；0.569,0.001；0.534,0.001；0.684,0.001；0.686,0.001)
3电镜下肾血管内皮组织的特点：替米沙坦、二甲双胍组大鼠肾小球滤过膜病变较模型组大鼠减轻,见少部分血管内皮增生,基底膜轻度增厚,足突接近正常；细胞核、线粒体、内质网结构大致正常。
结论：本实验通过高脂饮食成功完成了对OLETF大鼠糖尿病并发肾血管内皮组织病变模型的建立。模型组OLETF雄性大鼠血清MCP-1表达增强,其肾小球滤过膜病变程度较重并与血清MCP-1的表达水平成正相关；肾素-血管紧张素系统(Renin-Angiotensin System),RAS阻断剂替米沙坦可抑制机体炎症反应,下调血清MCP-1的表达,改善高胆固醇血症、高低密度脂蛋白血症和胰岛素抵抗,进而保护其对机体肾脏微血管即肾小球滤过膜的损害。
Objecttives: Monocyte chemoattractant protein-1 (MCP-1) is a regulator of monocyte/macrophage migration and infiltration of the most important inflammatory chemokine. It could increase vascular endothelial injury through the expression of MCP-1,also induce vascular smooth muscel cell proliferation and migration. The formation of high glycation end product (AGE) in long-term high blood sugar and diabetic state, nitric oxide (NO) synthesis may be reduced or decreased activity to increase MCP-1 expression. MCP-1 may lead to endothelial dysfunction and induce vascular smooth muscle cell proliferation or migration which aggravate atherosclerotic lesions. In our experiment, our research was based on diabetic OLETF (otsuka long-evans tokushima fatty) nephropathy rats and the department of LETO control rats:Effect of telmisartan on renal microvascular disease in diabetic rats induced by serum MCP-1.
Methods:Otsuka, Japan Insitute supplied 24 male OLETE rats and the fellow 10 male LETO normal non-diabetic control group rats which were 4-week old. All rats are off weight 150-200g. The male OLETF rats were fed with high-fat diet and the male LETO control group rats were always fed with normal diet. All rats were divided into four groups according to different treatment:24 male OLETF diabetic rats were randomly divided into three groups, telmisartangroup(MT)、the metformin group(MET)、the model without making intervention group(MX)and without intervention of normal non-diabetic control group(NC). All rats were sacrificed after fasting for 12 hours, Centrifugalled separation of serum and renal tissue. MCP-1,FFA,FINS,FBG,TC,TG,LDL,HDL,BUN,Scr and 24h urine protein level in plasma were measured. The glomerular filtration membrane of the ultrastructures in all rats were observed by the transmission electron microscopy. MCP-1 expression levels of renal vascular endothelial tissue were detected by immunohistochemistry. HOMA-IRI=(FINS×FBG)÷22.5.Four groups were compared between the above indicators, also compared the MCP-1 with FFA,FINS,FBG,TC,TG,LDL,HDL correlation between biochemical indicators.
Results:1. Serum MCP-1 levels among groups:Compared with the control group [(30.91±4.42)pg/ml], the serum MCP-1 levels in diabetics model group [(44.92±7.21)pg/ml] increased (P<0.05); Compared with drug intervention telmisartan group [(32.70±6.71)pg/ml]、metformin group [(33.33±4.47)pg/ml], the serum MCP-1 levels in diabetics model group [(44.92±7.21)pg/ml] increased (P＜0.05).
2. Correlation analysis:Linear correlation ananlysis showed that serum MCP-1 levels had positive relationship with the levels FFA,TC,TG,LDL,FINS,HOMA-IR. (r,p 0.454,0.040;0.315,0.040;0.292,0.046;0.418,0.007;0.360,0.022;0.527,0.001)
3. Electron microscopy features of renal vascular endothelium:The glomerular filtration membrane disease of the telmisartan group and other two groups rats are improved better than the model group; observed small vascular endothelial proliferation, mild basement membrane thickening, near normal foot progress, nucleus, mitochondria, endoplasmic reticulum structure.
Conclusions:We successfully got the diabetic OLETF rats with renal vascular endothelial dysfunction model through high diet. Blood monocyte chemoattractant protein-1 (MCP-1) expression increased greatly in diabetic OLETF male rats. It also involved in the pathogenesis of disease in glomerular filtration module, and MCP-1 expression correlates positives with glomerular filtration mold disease. Renin-angiotensin system (RAS) blockers telmisartan could inhibit the inflammatory response, decrease MCP-1 expression improve blood lipids and insulin resistance; thus protected glomerular flitration membrane of renal microvascular damaga.
方法：由日本大冢研究所提供的OLETF (Otsuka Long-Evans Tokushima Fatty)雄性4周龄大鼠24只及正常无糖尿病对照组LETO (Long-Evans Tokushima)雄性4周龄大鼠10只,体质量均为150-200g。OLETF雄性大鼠予以高脂饮食喂养和正常对照组LETO大鼠予以普通饲料喂养,根据对大鼠的不同处理方法分为四组：OLETF模型组大鼠随机分为三组,即替米沙坦组(MT),二甲双胍组(MET),未做干预的模型组(MX)及无干预的正常无糖尿病对照组(NC)。干预42周后,全部动物禁食12小时后处死离心分离血清及肾周组织。检测血清MCP-1、FFA、FINS、FBG、TC、TG、LDL、HDL、BUN、Cr及24h尿蛋白水平,用透射电子显微镜观察大鼠肾小球滤过膜的超微结构；采用免疫组化法检测肾血管内皮组织MCP-1的表达水平；胰岛素抵抗指数(HOMA-IR)=(FINS×FBG)÷22.5;比较各组之间以上各指标的差异,并比较MCP-1与FFA、FINS、FBG、TC、TG、LDL、HDL等生化指标之间的相关性；所有结果均采用SPSS15.0软件分析处理。
结果：1组间大鼠血清MCP-1水平比较：与正常对照组[(30.91±4.42)pg/ml]比较,模型组大鼠血清MCP-1水平[(44.92±7.21)pg/ml]增高(P<0.05)；与药物干预替米沙坦组[(32.70±6.71)pg/ml]、二甲双胍组[(33.33±4.47)pg/ml]比较,模型组大鼠血清MCP-1水平[(44.92±7.21)pg/ml]增高(P<0.05)。
2相关性分析：直线相关分析显示血清MCP-1水平与FFA、TC、TG、LDL、FINS、HOMA-IR指数呈正相关(r、P分别为0.686,0.001；0.537,0.001；0.569,0.001；0.534,0.001；0.684,0.001；0.686,0.001)
3电镜下肾血管内皮组织的特点：替米沙坦、二甲双胍组大鼠肾小球滤过膜病变较模型组大鼠减轻,见少部分血管内皮增生,基底膜轻度增厚,足突接近正常；细胞核、线粒体、内质网结构大致正常。
结论：本实验通过高脂饮食成功完成了对OLETF大鼠糖尿病并发肾血管内皮组织病变模型的建立。模型组OLETF雄性大鼠血清MCP-1表达增强,其肾小球滤过膜病变程度较重并与血清MCP-1的表达水平成正相关；肾素-血管紧张素系统(Renin-Angiotensin System),RAS阻断剂替米沙坦可抑制机体炎症反应,下调血清MCP-1的表达,改善高胆固醇血症、高低密度脂蛋白血症和胰岛素抵抗,进而保护其对机体肾脏微血管即肾小球滤过膜的损害。
Objecttives: Monocyte chemoattractant protein-1 (MCP-1) is a regulator of monocyte/macrophage migration and infiltration of the most important inflammatory chemokine. It could increase vascular endothelial injury through the expression of MCP-1,also induce vascular smooth muscel cell proliferation and migration. The formation of high glycation end product (AGE) in long-term high blood sugar and diabetic state, nitric oxide (NO) synthesis may be reduced or decreased activity to increase MCP-1 expression. MCP-1 may lead to endothelial dysfunction and induce vascular smooth muscle cell proliferation or migration which aggravate atherosclerotic lesions. In our experiment, our research was based on diabetic OLETF (otsuka long-evans tokushima fatty) nephropathy rats and the department of LETO control rats:Effect of telmisartan on renal microvascular disease in diabetic rats induced by serum MCP-1.
Methods:Otsuka, Japan Insitute supplied 24 male OLETE rats and the fellow 10 male LETO normal non-diabetic control group rats which were 4-week old. All rats are off weight 150-200g. The male OLETF rats were fed with high-fat diet and the male LETO control group rats were always fed with normal diet. All rats were divided into four groups according to different treatment:24 male OLETF diabetic rats were randomly divided into three groups, telmisartangroup(MT)、the metformin group(MET)、the model without making intervention group(MX)and without intervention of normal non-diabetic control group(NC). All rats were sacrificed after fasting for 12 hours, Centrifugalled separation of serum and renal tissue. MCP-1,FFA,FINS,FBG,TC,TG,LDL,HDL,BUN,Scr and 24h urine protein level in plasma were measured. The glomerular filtration membrane of the ultrastructures in all rats were observed by the transmission electron microscopy. MCP-1 expression levels of renal vascular endothelial tissue were detected by immunohistochemistry. HOMA-IRI=(FINS×FBG)÷22.5.Four groups were compared between the above indicators, also compared the MCP-1 with FFA,FINS,FBG,TC,TG,LDL,HDL correlation between biochemical indicators.
Results:1. Serum MCP-1 levels among groups:Compared with the control group [(30.91±4.42)pg/ml], the serum MCP-1 levels in diabetics model group [(44.92±7.21)pg/ml] increased (P<0.05); Compared with drug intervention telmisartan group [(32.70±6.71)pg/ml]、metformin group [(33.33±4.47)pg/ml], the serum MCP-1 levels in diabetics model group [(44.92±7.21)pg/ml] increased (P＜0.05).
2. Correlation analysis:Linear correlation ananlysis showed that serum MCP-1 levels had positive relationship with the levels FFA,TC,TG,LDL,FINS,HOMA-IR. (r,p 0.454,0.040;0.315,0.040;0.292,0.046;0.418,0.007;0.360,0.022;0.527,0.001)
3. Electron microscopy features of renal vascular endothelium:The glomerular filtration membrane disease of the telmisartan group and other two groups rats are improved better than the model group; observed small vascular endothelial proliferation, mild basement membrane thickening, near normal foot progress, nucleus, mitochondria, endoplasmic reticulum structure.
Conclusions:We successfully got the diabetic OLETF rats with renal vascular endothelial dysfunction model through high diet. Blood monocyte chemoattractant protein-1 (MCP-1) expression increased greatly in diabetic OLETF male rats. It also involved in the pathogenesis of disease in glomerular filtration module, and MCP-1 expression correlates positives with glomerular filtration mold disease. Renin-angiotensin system (RAS) blockers telmisartan could inhibit the inflammatory response, decrease MCP-1 expression improve blood lipids and insulin resistance; thus protected glomerular flitration membrane of renal microvascular damaga.
引文
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