实验性糖尿病大鼠早期肾脏病变的代谢组学研究
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摘要
第一部分实验性糖尿病大鼠模型的建立和肾脏早期病变的鉴定
目的:建立实验性糖尿病大鼠动物模型,观察其肾脏早期病变病程中不同时间点的病理生理特点及变化趋势,并对早期肾脏病变程度加以鉴定,为后期代谢组学研究提供可靠的实验模型。
方法:1、健康SD大鼠84只,分为正常对照组36只,糖尿病模型组48只。腹腔注射STZ建立糖尿病模型,2次测定随机血糖大于16.7mmol/L,定义为糖尿病大鼠。实验观察时间为24周,分别于4、8、12、16、20及24周,留取血、尿、肾脏组织标本。2、测定体重、血糖、24小时尿蛋白、血尿肌酐和肾脏重量,计算肌酐清除率及肾重/体重。3、肾脏组织形态学观察采用HE染色光镜检查。
结果:1、注射STZ 48-72小时后大鼠开始出现多尿、多饮症状,并伴有活动减少。2、糖尿病大鼠较正常对照组血糖明显升高,尿量明显增加,体重明显减轻,在各个时间点上均具有统计学意义;两组24小时尿蛋白排出量、肾重/体重、肌酐清除率均有显著性差异。3、不同时间点亚组间比较:正常对照组血糖、尿量无明显差异,体重随时间延长逐渐增加;糖尿病组各时间点上大鼠体重随时间延长未见明显增加,血糖及尿量组间有所差异,但并未体现出具有一定规律的变化趋势。正常组大鼠24小时尿蛋白排出量、肾重/体重、肌酐清除率均无明显差异,DM组24小时尿蛋白排出量呈现出随病程延长逐渐增加的趋势;肾重/体重各时间点上有差异,但未见明显的随病程进展的变化趋势;肌酐清除率呈现先上升后下降的趋势。4、光镜下,NC组大鼠肾小球结构正常,DN可见肾小球基底膜增厚,而部分DM组大鼠仅见肾小球肿胀,而无明显的基底膜增厚。随病程进展未见DM大鼠肾脏有时间特异特征性病理学改变,但随病程进展出现的肾脏病变程度不同,基底膜增厚的程度逐渐加重,并且出现明显肾脏病理性变化的大鼠的数目渐增多。
结论:腹腔注射STZ可成功诱导糖尿病大鼠模型,随时间延长24小时尿蛋白排出量及肌酐清除率呈现规律性变化,于24周时肾脏出现明显的病理性改变。因此,STZ诱导的糖尿病大鼠模型可以作为研究糖尿病早期肾脏病变的理想动物模型。
第二部分糖尿病大鼠肾脏早期病变的代谢组学研究
目的:通过对糖尿病大鼠早期肾脏病变模型血、尿标本的代谢组学研究,寻找糖尿病及糖尿病早期肾脏病变的特征性代谢产物,探寻高血糖对肾脏病变的分子机制。
方法:1、LC/MS方法检测动物模型血、尿标本的所有小分子代谢产物,描记代谢谱;确定糖尿病早期肾脏病变阳性和阴性病例,采用PLS-DA和OPLS对代谢组数据分析,根据所得小分子物质的质量数和保留时间,预测与糖尿病早期肾脏病变相关的特征性代谢产物的分子结构,并定量分析其在各组间水平。2根据获得的特征性代谢产物的信息,依据支持向量机理论,以已确定诊断肾脏病变的大鼠代谢组数据为训练集,建立糖尿病大鼠早期肾脏病变的疾病诊断预测数学模型,对尿蛋白排出量、KW/BW、Ccr不能明确诊断大鼠进行疾病预测,结果与病理诊断相比较,评价Maker及诊断预测模型的价值。
结果:1、DM与NC组大鼠血清的代谢指纹图谱有显著不同,质量数分别为588.323,566.339,540.321,568.353,303.229,554.341,564.321,339.228,327.229的小分子代谢产物在两组的水平明显差异。2、在糖尿病早期肾脏病变阳性及阴性的病例中,血清代谢组学分析获得特征性的小分子物质,质核比分别为342.1831,314.2246,614.1820,399.3349,450.1936,130.0630,670.3843,342.1162,822.4051,432.3240,503.1791,898.5402,445.1710,489.1999。尿液标本筛选出的小分子,质核比为700.1428,131.0582,382.1310,552.4331。按荷载图提示的对区分糖尿病早期肾脏病变的贡献大小、与肾病的相关性及物质源性,最终定量分析内源性物质亚铁血红素HEME和乙酰氨基丙酸。3、以上述2个marker的指纹图谱信息作为参数,建立疾病预测的数学模型,对28只疑诊肾脏病变的大鼠进行诊断预测,两种预测方法结果与病理诊断的阳性吻合率均为94.12%,阴性吻合率是87.50%和81.25%。
结论:LC/MS联用的分析技术是研究糖尿病早期肾脏病变动物模型的有效工具;亚铁血红素与5-氨基乙酰丙酸水平在糖尿病早期肾脏病变的病理状态下有明显改变,两者在糖尿病早期肾脏病变的发病机制中可能起到重要作用。
第三部分通络方药对糖尿病大鼠早期肾脏病变的保护作用
目的:比较通络方药不同给药时间即预防性干预和治疗性干预对糖尿病大鼠早期肾脏病变的保护作用及其疗效,并从代谢组学角度探讨通络方药可能的作用机制。
方法:实验动物48只,随机分为2组,每组包括NC组6只,DM组8只,TLR组10只,观察时间分别为12W和24W。两组TLR大鼠分别于DM造模成功后立即和模型成功后第12周后给予TLR干预,分别定义为预防性给药组和治疗性给药组。于即定时间处死两组大鼠,并测定24小时尿蛋白排出量,血肌酐、尿肌酐及肾重计算KW/BW、Ccr;取肾脏组织进行光镜HE染色病理学检查。留大鼠血、尿标本代谢组分析。
结果:1、预防性及治疗性药物干预抑制糖尿病大鼠早期肾脏病变所引起的尿蛋白排出和肌酐清除率升高。2、预防性给药对糖尿病大鼠24小时尿量、尿蛋白排出量、肌酐清除率的改善率分别为59.45%、48.52%、51.40%;治疗性给药组相应指标改善率为21.59%、38.26%、44.29%。3、无论是预防性或是治疗性药物干预,给药组与糖尿病组代谢产物谱有明显变化。其中,HEME和氨基乙酰丙酸在血清和尿液标本中的含量下降。
结论:1、对糖尿病大鼠预防性给药可明显保护肾脏,使其尿蛋白于12周时仍保持正常水平;2、治疗性药物干预可有效保护肾脏,降低肾脏24尿蛋白的排出量;3、预防性给药对尿量、尿蛋白、肌酐清除率的改善作用略优于治疗性给药;4、通络方药干预前后代谢产物发生变化,且特征性的HEME和ALA有所下降,提示线粒体应激损伤可能减轻。
PartⅠEstablishment of diabetic rats model and identification early diabetic nephropathy
Objective To establish a experimental diabetic rats model observe and identify the early kidney damage features and change trend during desease process in order to provide a good experimental model for the Study of metabonomics.
Methods(1) 84 health SD rats were divided into normal NC group and DM group. Intraperitoneal injection of STZ for latter,abdominal aortic blood before take away the kidney at 4,8,12,16,20 and 24 weeks respectively.(2) Determine body weight,blood glucose,24-hour urinary protein,Ccr and KW/BW.(3) Renal morphology observed by light microscopy.
Results 1) symptoms of more urine and drink and activities reduction appear after STZ injection 48-72 hours.2 random blood glucose higher than 16.7 mmol/L,defined as diabetes.2) diabetes mellitus model rats charactered as increased blood sugar and urine output,reduced body weight;between the two groups 24-hour urinary protein excretion, KW/BW,Ccr were significantly different.3) at different time points:no significant difference in blood sugar,urine and body weight at different time points in NC group,;DM group rats weight,blood glucose,urine have no a marked increase during the process. Normal rats 24-hour urinary protein excretion,KW/BW,Ccr had no significant difference, 24-hour urinary protein excretion show a gradual increase with disease proceeding in the model group,and KW/BW in each time point are different,but no obvious trend,Ccr show increase first and decline in 16 weeks.4) glomerular structure in NC is normal,and glomerular basement membrane thickening,in DN.some DM rats glomerular only see swelling,but no obvious thickening of the basement membrane.
Conclusion Intraperitoneal-injection-STZ-induced diabetic rats is a successful model.In the course of 24 weeks,24-hour urinary protein excretion and creatinine clearance rate changes regularly.Therefore,STZ-induced diabetic rat model can be used as study of early diabetic kidney damage ideal animal model.
PartⅡMetabonomics on early diabetic nephropathy
Objective:To find diabetes and early diabetic kidney damage characteristic metabolites through Metabonomic Analysis.
Methods:(1)Samples collection same to the first part.(2) detect all small molecule metabolites by LC/MS,analysis data by PLS-DA,and selected some metabolites based on a structure identification in the end.(3)According to the metabolites,combinating SVM,establish early renal damage of diabetic rats prediction model.
Results:1) metabolites are difference between NC and DM group.There are quality mumber of 588.323,566.339,540.321,568.353,303.229,554.341,564.321,339.228, 327.229 are selected respectively,.2) more than 10 diabetic nephropathy early renal damage makers are selected and HEME and 5-acetyl-propionate are indentified by structure analysis.3) the 28 suspected diagnosis of early diabetic kidney damage in rats forecast results are coincidence with the pathological diagnosis with 82.7%by disease prediction model established.
Conclusion:Metabonomics is a good technology to study diabetic kidney damage HEME and 5-Amino are different significantly before and after disease,they may play an important role in early diabetic nephropathy.
PartⅢProtection of Tongluo Recipe on early diabetic kidney damage
Objective:compare Tongluo Recipe effection between two groups,and find possible mechanism of protection for diabetic nephropathy.
Methods:1) Experimental animals 48,including two groups of 12W and 24W respectively, each one include NC Group 6,DM Group 8,TL Group10.Preventive group rats were administrated TLR immediately after glucose increasing,,while therapeutic group rats start to drug in the 12 weeks after the successful model set up.Determination of 24- hour urinary protein excretion,KW/BW,Ccr,and light microscopy HE staining histopathological examination,and metabonomics analysis.
Results:1) Preventive and therapeutic drug intervention on early kidney damage in diabetic rats,show the improvement on urinary protein,Ccr,and KW/BW.Efeect of prevetion treatment is better than therapeutic intervention.2) Whether preventive or therapeutic intervention,metabolites of intervention and DM group are different in spectrum.
Conclusion:1) Preventive group diabetic rats could maintain urinary protein level as normal in 12 weeks.Therapeutic intervention also can protect the kidneys in decreased exclusion of urinary protein.Former is slightly better than the latter in improvement of urine protein 2) After Tongluo Prescription,metabolites significantly changes in TLR and other rats.The change of HEME and 5-amino acid,is obviously.
目的:建立实验性糖尿病大鼠动物模型,观察其肾脏早期病变病程中不同时间点的病理生理特点及变化趋势,并对早期肾脏病变程度加以鉴定,为后期代谢组学研究提供可靠的实验模型。
方法:1、健康SD大鼠84只,分为正常对照组36只,糖尿病模型组48只。腹腔注射STZ建立糖尿病模型,2次测定随机血糖大于16.7mmol/L,定义为糖尿病大鼠。实验观察时间为24周,分别于4、8、12、16、20及24周,留取血、尿、肾脏组织标本。2、测定体重、血糖、24小时尿蛋白、血尿肌酐和肾脏重量,计算肌酐清除率及肾重/体重。3、肾脏组织形态学观察采用HE染色光镜检查。
结果:1、注射STZ 48-72小时后大鼠开始出现多尿、多饮症状,并伴有活动减少。2、糖尿病大鼠较正常对照组血糖明显升高,尿量明显增加,体重明显减轻,在各个时间点上均具有统计学意义;两组24小时尿蛋白排出量、肾重/体重、肌酐清除率均有显著性差异。3、不同时间点亚组间比较:正常对照组血糖、尿量无明显差异,体重随时间延长逐渐增加;糖尿病组各时间点上大鼠体重随时间延长未见明显增加,血糖及尿量组间有所差异,但并未体现出具有一定规律的变化趋势。正常组大鼠24小时尿蛋白排出量、肾重/体重、肌酐清除率均无明显差异,DM组24小时尿蛋白排出量呈现出随病程延长逐渐增加的趋势;肾重/体重各时间点上有差异,但未见明显的随病程进展的变化趋势;肌酐清除率呈现先上升后下降的趋势。4、光镜下,NC组大鼠肾小球结构正常,DN可见肾小球基底膜增厚,而部分DM组大鼠仅见肾小球肿胀,而无明显的基底膜增厚。随病程进展未见DM大鼠肾脏有时间特异特征性病理学改变,但随病程进展出现的肾脏病变程度不同,基底膜增厚的程度逐渐加重,并且出现明显肾脏病理性变化的大鼠的数目渐增多。
结论:腹腔注射STZ可成功诱导糖尿病大鼠模型,随时间延长24小时尿蛋白排出量及肌酐清除率呈现规律性变化,于24周时肾脏出现明显的病理性改变。因此,STZ诱导的糖尿病大鼠模型可以作为研究糖尿病早期肾脏病变的理想动物模型。
第二部分糖尿病大鼠肾脏早期病变的代谢组学研究
目的:通过对糖尿病大鼠早期肾脏病变模型血、尿标本的代谢组学研究,寻找糖尿病及糖尿病早期肾脏病变的特征性代谢产物,探寻高血糖对肾脏病变的分子机制。
方法:1、LC/MS方法检测动物模型血、尿标本的所有小分子代谢产物,描记代谢谱;确定糖尿病早期肾脏病变阳性和阴性病例,采用PLS-DA和OPLS对代谢组数据分析,根据所得小分子物质的质量数和保留时间,预测与糖尿病早期肾脏病变相关的特征性代谢产物的分子结构,并定量分析其在各组间水平。2根据获得的特征性代谢产物的信息,依据支持向量机理论,以已确定诊断肾脏病变的大鼠代谢组数据为训练集,建立糖尿病大鼠早期肾脏病变的疾病诊断预测数学模型,对尿蛋白排出量、KW/BW、Ccr不能明确诊断大鼠进行疾病预测,结果与病理诊断相比较,评价Maker及诊断预测模型的价值。
结果:1、DM与NC组大鼠血清的代谢指纹图谱有显著不同,质量数分别为588.323,566.339,540.321,568.353,303.229,554.341,564.321,339.228,327.229的小分子代谢产物在两组的水平明显差异。2、在糖尿病早期肾脏病变阳性及阴性的病例中,血清代谢组学分析获得特征性的小分子物质,质核比分别为342.1831,314.2246,614.1820,399.3349,450.1936,130.0630,670.3843,342.1162,822.4051,432.3240,503.1791,898.5402,445.1710,489.1999。尿液标本筛选出的小分子,质核比为700.1428,131.0582,382.1310,552.4331。按荷载图提示的对区分糖尿病早期肾脏病变的贡献大小、与肾病的相关性及物质源性,最终定量分析内源性物质亚铁血红素HEME和乙酰氨基丙酸。3、以上述2个marker的指纹图谱信息作为参数,建立疾病预测的数学模型,对28只疑诊肾脏病变的大鼠进行诊断预测,两种预测方法结果与病理诊断的阳性吻合率均为94.12%,阴性吻合率是87.50%和81.25%。
结论:LC/MS联用的分析技术是研究糖尿病早期肾脏病变动物模型的有效工具;亚铁血红素与5-氨基乙酰丙酸水平在糖尿病早期肾脏病变的病理状态下有明显改变,两者在糖尿病早期肾脏病变的发病机制中可能起到重要作用。
第三部分通络方药对糖尿病大鼠早期肾脏病变的保护作用
目的:比较通络方药不同给药时间即预防性干预和治疗性干预对糖尿病大鼠早期肾脏病变的保护作用及其疗效,并从代谢组学角度探讨通络方药可能的作用机制。
方法:实验动物48只,随机分为2组,每组包括NC组6只,DM组8只,TLR组10只,观察时间分别为12W和24W。两组TLR大鼠分别于DM造模成功后立即和模型成功后第12周后给予TLR干预,分别定义为预防性给药组和治疗性给药组。于即定时间处死两组大鼠,并测定24小时尿蛋白排出量,血肌酐、尿肌酐及肾重计算KW/BW、Ccr;取肾脏组织进行光镜HE染色病理学检查。留大鼠血、尿标本代谢组分析。
结果:1、预防性及治疗性药物干预抑制糖尿病大鼠早期肾脏病变所引起的尿蛋白排出和肌酐清除率升高。2、预防性给药对糖尿病大鼠24小时尿量、尿蛋白排出量、肌酐清除率的改善率分别为59.45%、48.52%、51.40%;治疗性给药组相应指标改善率为21.59%、38.26%、44.29%。3、无论是预防性或是治疗性药物干预,给药组与糖尿病组代谢产物谱有明显变化。其中,HEME和氨基乙酰丙酸在血清和尿液标本中的含量下降。
结论:1、对糖尿病大鼠预防性给药可明显保护肾脏,使其尿蛋白于12周时仍保持正常水平;2、治疗性药物干预可有效保护肾脏,降低肾脏24尿蛋白的排出量;3、预防性给药对尿量、尿蛋白、肌酐清除率的改善作用略优于治疗性给药;4、通络方药干预前后代谢产物发生变化,且特征性的HEME和ALA有所下降,提示线粒体应激损伤可能减轻。
PartⅠEstablishment of diabetic rats model and identification early diabetic nephropathy
Objective To establish a experimental diabetic rats model observe and identify the early kidney damage features and change trend during desease process in order to provide a good experimental model for the Study of metabonomics.
Methods(1) 84 health SD rats were divided into normal NC group and DM group. Intraperitoneal injection of STZ for latter,abdominal aortic blood before take away the kidney at 4,8,12,16,20 and 24 weeks respectively.(2) Determine body weight,blood glucose,24-hour urinary protein,Ccr and KW/BW.(3) Renal morphology observed by light microscopy.
Results 1) symptoms of more urine and drink and activities reduction appear after STZ injection 48-72 hours.2 random blood glucose higher than 16.7 mmol/L,defined as diabetes.2) diabetes mellitus model rats charactered as increased blood sugar and urine output,reduced body weight;between the two groups 24-hour urinary protein excretion, KW/BW,Ccr were significantly different.3) at different time points:no significant difference in blood sugar,urine and body weight at different time points in NC group,;DM group rats weight,blood glucose,urine have no a marked increase during the process. Normal rats 24-hour urinary protein excretion,KW/BW,Ccr had no significant difference, 24-hour urinary protein excretion show a gradual increase with disease proceeding in the model group,and KW/BW in each time point are different,but no obvious trend,Ccr show increase first and decline in 16 weeks.4) glomerular structure in NC is normal,and glomerular basement membrane thickening,in DN.some DM rats glomerular only see swelling,but no obvious thickening of the basement membrane.
Conclusion Intraperitoneal-injection-STZ-induced diabetic rats is a successful model.In the course of 24 weeks,24-hour urinary protein excretion and creatinine clearance rate changes regularly.Therefore,STZ-induced diabetic rat model can be used as study of early diabetic kidney damage ideal animal model.
PartⅡMetabonomics on early diabetic nephropathy
Objective:To find diabetes and early diabetic kidney damage characteristic metabolites through Metabonomic Analysis.
Methods:(1)Samples collection same to the first part.(2) detect all small molecule metabolites by LC/MS,analysis data by PLS-DA,and selected some metabolites based on a structure identification in the end.(3)According to the metabolites,combinating SVM,establish early renal damage of diabetic rats prediction model.
Results:1) metabolites are difference between NC and DM group.There are quality mumber of 588.323,566.339,540.321,568.353,303.229,554.341,564.321,339.228, 327.229 are selected respectively,.2) more than 10 diabetic nephropathy early renal damage makers are selected and HEME and 5-acetyl-propionate are indentified by structure analysis.3) the 28 suspected diagnosis of early diabetic kidney damage in rats forecast results are coincidence with the pathological diagnosis with 82.7%by disease prediction model established.
Conclusion:Metabonomics is a good technology to study diabetic kidney damage HEME and 5-Amino are different significantly before and after disease,they may play an important role in early diabetic nephropathy.
PartⅢProtection of Tongluo Recipe on early diabetic kidney damage
Objective:compare Tongluo Recipe effection between two groups,and find possible mechanism of protection for diabetic nephropathy.
Methods:1) Experimental animals 48,including two groups of 12W and 24W respectively, each one include NC Group 6,DM Group 8,TL Group10.Preventive group rats were administrated TLR immediately after glucose increasing,,while therapeutic group rats start to drug in the 12 weeks after the successful model set up.Determination of 24- hour urinary protein excretion,KW/BW,Ccr,and light microscopy HE staining histopathological examination,and metabonomics analysis.
Results:1) Preventive and therapeutic drug intervention on early kidney damage in diabetic rats,show the improvement on urinary protein,Ccr,and KW/BW.Efeect of prevetion treatment is better than therapeutic intervention.2) Whether preventive or therapeutic intervention,metabolites of intervention and DM group are different in spectrum.
Conclusion:1) Preventive group diabetic rats could maintain urinary protein level as normal in 12 weeks.Therapeutic intervention also can protect the kidneys in decreased exclusion of urinary protein.Former is slightly better than the latter in improvement of urine protein 2) After Tongluo Prescription,metabolites significantly changes in TLR and other rats.The change of HEME and 5-amino acid,is obviously.
引文
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