姜黄素对2型糖尿病大鼠肾脏改变的作用机制研究
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摘要
目的糖尿病肾病(diabetic nephropathy, DN)是一种以血管损害为主的肾小球病变,是糖尿病(diabetes mellitus, DM)常见慢性并发症之一,也是导致终末期肾病(end-stage renal disease, ESRD)的主要原因之一。目前大量实验发现“氧化应激-炎症-氧化应激”这一恶性循环导致的血管内皮功能不全在糖尿病血管并发症发病机制中占有重要地位。姜黄素是一种植物来源的抗氧化剂,具有广泛的生物活性,在肾脏它能发挥抗纤维化的作用,其对肾脏炎症病变的影响及其机制尚不十分清楚。本实验构建2型糖尿病大鼠模型,通过姜黄素给药干预,观察姜黄素对实验动物肾组织形态学变化以及单核巨噬细胞浸润的影响、测定其对核因子κB(nuclear factorκB, NFκB)、Toll样受体2(Toll-like receptor 2, TLR2 )、骨桥蛋白(osteopontin, OPN)表达的影响,初步探讨其对糖尿病肾病治疗作用机理,为其应用于DN临床治疗提供了理论依据。
方法40只清洁级SD雄性大鼠,体重200～250g,随机分为假手术组和手术组。手术组大鼠切除左侧肾脏,术后2周手术组大鼠随机分为单切组及实验组。实验组大鼠用于造模,选造模成功大鼠,再随机分为2组,糖尿病组、姜黄素治疗组。确定成模后第2天,姜黄素治疗组以姜黄素200mg/kg/d灌胃,同时其余三组每日以1%羧甲基纤维素钠灌胃。给药后6周处死所有大鼠,取右肾组织进行病理染色,在光镜下观察肾组织形态学变化;免疫组化方法检测CD68、NFκBp65蛋白的表达;并用RT-PCR方法检测肾组织OPN和TLR2mRNA的表达。
结果(1)肾组织PAS染色显示:糖尿病组肾小球基底膜增厚,ECM增多,系膜区扩张,肾小球内可见单核细胞浸润;与之相比,姜黄素治疗组上述病变明显减轻。对各组系膜区面积/肾小球面积的比值进行比较发现:假手术组与单切组间比较差异无显著性;与假手术组和单切组相比,糖尿病组比值明显增加(p<0.01),姜黄素治疗比值低于糖尿病组(p<0.05)。(2)免疫组化结果显示:糖尿病组NF-κB /p65蛋白胞核内表达增加,CD68阳性细胞数增多,与假手术组和单切组相比有统计学意义(p<0.01)。与糖尿病组相比,姜黄素治疗组上述表达减轻(p<0.05)。(3)RT-PCR结果显示:各组大鼠肾组织中TLR2mRNA均有不同程度的表达,假手术组和单切组间比较差异无显著性,糖尿病组、姜黄素组表达明显增多(p<0.01),且两组间比较差异无显著性。与假手术组和单切组相比,糖尿病组OPNmRNA表达明显上调(p<0.01);与糖尿病组相比,姜黄素组表达减少(p<0.05)。
结论(1)姜黄素可以明显改善糖尿病大鼠的肾脏病理变化,减少肾组织中巨噬细胞的浸润,延缓肾纤维化进程;(2)姜黄素能抑制NF-κB /p65蛋白核转导,抑制肾组织中OPNmRNA的表达,但对TLR2的表达没有抑制作用;(3)姜黄素缓解糖尿病肾病肾组织炎性病变的作用可能与其下调OPNmRNA的表达进而抑制NFκB p65的核转导有关,对TLR2介导的NFκB激活姜黄素没有抑制作用。
Objective: Diabetic nephropathy (DN) is a glomerulonephritis with main and characteristic vascular lesion and a common chronic complication of diabetes mellitus which is a key protopathy resulting in end-stage kidney disease. It has been shown that oxidative stress-inflammation-oxidative stress which is a vicious circle leads to endothelial dysfunction (ED) which plays a critical role in the vascular complications associated with diabetes. Curcumin is a vegetal antioxidant possessing extensive biological activity and renoprotective for alleviating renal fibrosis, but its effect on inflammation in kidney and the underlying mechanisms are still unclear. In this study, we construct a rat model of Type 2 diabetes mellitus and observe the effect of curcumin on inflammation and expression of CD68, NFκB, TLR2, OPN in DN kidneys. On the basis of those data we try to illustrate the possible mechanism underlying that and provide some evidence for its prospective use in treatment of DN.
Method: Forty Sprague-Dawley male rats weighed 200 to 250g and were randomly divided into sham operation group (SHAM) and operation group. The operation group rats underwent unilateral nephrectomy. Two weeks after uninephrectomy four group, these uninephrectomized rats were randomly divided into uninephrectomy control group (1/2Nx) and model group. Model group rats were used to construct models of Type 2 diabetes mellitus (T2DM). Those successful model rats were divided into DM group and curcumin-administration group (DM+Cur). After identification, DM+Cur rats were fed sodium carboxymethycellulose solid containing curcumin (200mg·kg-1·d-1) and other rats fed sodium carboxymethycellulose solid with same concentration. The rats were killed six weeks later and renal tissues were examined by microscope. Immunohistochemistry was applied to determine the protein expressions of CD68 and NFκBp65, the mRNA expressions of OPN and TLR2 were detected semiquantitatively with reverse transcription-polymerase chain reaction.
Results: (1) PAS staining of the renal tissue revealed that thickening of glomerular basement membrane, mesangial cell hyperplasia, expansion of mesangial matrix, infiltration of monocyte in DM group. Comparied with it, the lesion in DM+Cur group was attenuated. To mention the area ratios of mesangial region vs the whole glomerular there was no significant difference between SHAM group and 1/2Nx group. The ratios in DM group were significantly elevated (p<0.01), while in DM+Cur group were lower than in DM group (p<0.05). (2) Immunohistochemistry showed in comparison with control group there were more NF-κBp65 protein expressed in nuclei and more CD68 positive cells in DM group. Compared with DM group, the expression and positive cells were deceased (p<0.05). (3) Renal expressions of TLR2 mRNA were significantly increased in DM group and DM+Cur group in comparison with control group (p<0.01), but there was no difference between them. OPN mRNA expression was significantly elevated in DM group than in control group, while the expression of DM+Cur group decreased (p<0.05).
Conclusion: (1) We observed that in rat model of T2DM, curcumin improved the histological lesion and prevent the development of glomerular fibrosis. (2) Curcumin can inhibit the NF-κBp65 transduction into nuclei and over expression of OPN, which may consequently result in moderate infiltration of monocyte, but not suppress TLR2mRNA expression. (3) Curcumin may alleviate the inflammational process by inhibiting NFκBp65 transduction into nuclei and down-regulating OPN mRNA expression.
方法40只清洁级SD雄性大鼠,体重200～250g,随机分为假手术组和手术组。手术组大鼠切除左侧肾脏,术后2周手术组大鼠随机分为单切组及实验组。实验组大鼠用于造模,选造模成功大鼠,再随机分为2组,糖尿病组、姜黄素治疗组。确定成模后第2天,姜黄素治疗组以姜黄素200mg/kg/d灌胃,同时其余三组每日以1%羧甲基纤维素钠灌胃。给药后6周处死所有大鼠,取右肾组织进行病理染色,在光镜下观察肾组织形态学变化;免疫组化方法检测CD68、NFκBp65蛋白的表达;并用RT-PCR方法检测肾组织OPN和TLR2mRNA的表达。
结果(1)肾组织PAS染色显示:糖尿病组肾小球基底膜增厚,ECM增多,系膜区扩张,肾小球内可见单核细胞浸润;与之相比,姜黄素治疗组上述病变明显减轻。对各组系膜区面积/肾小球面积的比值进行比较发现:假手术组与单切组间比较差异无显著性;与假手术组和单切组相比,糖尿病组比值明显增加(p<0.01),姜黄素治疗比值低于糖尿病组(p<0.05)。(2)免疫组化结果显示:糖尿病组NF-κB /p65蛋白胞核内表达增加,CD68阳性细胞数增多,与假手术组和单切组相比有统计学意义(p<0.01)。与糖尿病组相比,姜黄素治疗组上述表达减轻(p<0.05)。(3)RT-PCR结果显示:各组大鼠肾组织中TLR2mRNA均有不同程度的表达,假手术组和单切组间比较差异无显著性,糖尿病组、姜黄素组表达明显增多(p<0.01),且两组间比较差异无显著性。与假手术组和单切组相比,糖尿病组OPNmRNA表达明显上调(p<0.01);与糖尿病组相比,姜黄素组表达减少(p<0.05)。
结论(1)姜黄素可以明显改善糖尿病大鼠的肾脏病理变化,减少肾组织中巨噬细胞的浸润,延缓肾纤维化进程;(2)姜黄素能抑制NF-κB /p65蛋白核转导,抑制肾组织中OPNmRNA的表达,但对TLR2的表达没有抑制作用;(3)姜黄素缓解糖尿病肾病肾组织炎性病变的作用可能与其下调OPNmRNA的表达进而抑制NFκB p65的核转导有关,对TLR2介导的NFκB激活姜黄素没有抑制作用。
Objective: Diabetic nephropathy (DN) is a glomerulonephritis with main and characteristic vascular lesion and a common chronic complication of diabetes mellitus which is a key protopathy resulting in end-stage kidney disease. It has been shown that oxidative stress-inflammation-oxidative stress which is a vicious circle leads to endothelial dysfunction (ED) which plays a critical role in the vascular complications associated with diabetes. Curcumin is a vegetal antioxidant possessing extensive biological activity and renoprotective for alleviating renal fibrosis, but its effect on inflammation in kidney and the underlying mechanisms are still unclear. In this study, we construct a rat model of Type 2 diabetes mellitus and observe the effect of curcumin on inflammation and expression of CD68, NFκB, TLR2, OPN in DN kidneys. On the basis of those data we try to illustrate the possible mechanism underlying that and provide some evidence for its prospective use in treatment of DN.
Method: Forty Sprague-Dawley male rats weighed 200 to 250g and were randomly divided into sham operation group (SHAM) and operation group. The operation group rats underwent unilateral nephrectomy. Two weeks after uninephrectomy four group, these uninephrectomized rats were randomly divided into uninephrectomy control group (1/2Nx) and model group. Model group rats were used to construct models of Type 2 diabetes mellitus (T2DM). Those successful model rats were divided into DM group and curcumin-administration group (DM+Cur). After identification, DM+Cur rats were fed sodium carboxymethycellulose solid containing curcumin (200mg·kg-1·d-1) and other rats fed sodium carboxymethycellulose solid with same concentration. The rats were killed six weeks later and renal tissues were examined by microscope. Immunohistochemistry was applied to determine the protein expressions of CD68 and NFκBp65, the mRNA expressions of OPN and TLR2 were detected semiquantitatively with reverse transcription-polymerase chain reaction.
Results: (1) PAS staining of the renal tissue revealed that thickening of glomerular basement membrane, mesangial cell hyperplasia, expansion of mesangial matrix, infiltration of monocyte in DM group. Comparied with it, the lesion in DM+Cur group was attenuated. To mention the area ratios of mesangial region vs the whole glomerular there was no significant difference between SHAM group and 1/2Nx group. The ratios in DM group were significantly elevated (p<0.01), while in DM+Cur group were lower than in DM group (p<0.05). (2) Immunohistochemistry showed in comparison with control group there were more NF-κBp65 protein expressed in nuclei and more CD68 positive cells in DM group. Compared with DM group, the expression and positive cells were deceased (p<0.05). (3) Renal expressions of TLR2 mRNA were significantly increased in DM group and DM+Cur group in comparison with control group (p<0.01), but there was no difference between them. OPN mRNA expression was significantly elevated in DM group than in control group, while the expression of DM+Cur group decreased (p<0.05).
Conclusion: (1) We observed that in rat model of T2DM, curcumin improved the histological lesion and prevent the development of glomerular fibrosis. (2) Curcumin can inhibit the NF-κBp65 transduction into nuclei and over expression of OPN, which may consequently result in moderate infiltration of monocyte, but not suppress TLR2mRNA expression. (3) Curcumin may alleviate the inflammational process by inhibiting NFκBp65 transduction into nuclei and down-regulating OPN mRNA expression.
引文
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3.李新建,刘晓城.姜黄素调节小鼠免疫功能的研究.中国组织化学与细胞化学杂2005, 14 (2): 132-135.
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