益气活血中药复方三芪口服液对早期糖尿病肾病的影响
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摘要
目的:
探讨益气活血中药复方三芪口服液干预糖尿病肾病的起始点及肾保护作用机制研究。
方法:
临床部分:
病例来源:广东省中医院大学城医院的住院及门诊病人共58例。
诊断标准:
(1)西医诊断标准:
①糖尿病诊断标准:参照1999年WHO标准。
②糖尿病肾病分期标准:参照Mogensen标准及王海燕《肾脏病学》。
Ⅰ期:肾脏肥大和肾小球高滤过,此期肾脏结构正常。
Ⅱ期:运动后出现微量白蛋白尿,肾脏病理示肾小球毛细血管基底膜(GBM)增厚。
Ⅲ期:持续性微量白蛋白尿,尿白蛋白排泄率(UAER)在20～200μg/min或30～300mg/24h之间,肾脏病理示肾小球系膜基质增加及GBM明显增厚,又称早期糖尿病肾病或亚临床糖尿病肾病。
Ⅳ期:UAER＞200ug/min或持续尿蛋白＞500mg/24h,病理示肾小球系膜基质明显增加及GBM明显增厚,部分小球荒废,又称临床期糖尿病肾病或中期糖尿病肾病。
Ⅴ期:肾功能破坏,肾小球荒废,又称终末期糖尿病肾病。
(2)中医证型诊断标准:
参照2002年版《中药新药临床研究指导原则》中关于气虚证及血瘀证的辨证标准。
(3)症状积分标准:
症状按无、轻、中、重记0、1、2、3分,舌脉记“有”为1分,“无”为0分。
纳入标准:
(1)符合以上中西医诊断标准;
(2)血糖:FPG≤7.0mmol/L 2HPG≤10.0mmol/L,病情稳定二周以上;
(3)蛋白尿:24h尿蛋白定量≤0.3g,UAER＜200ug/min。
同时具备以上三条方可纳入临床试验。
排除标准:
(1)排除其它原发及继发性原因所致蛋白尿;
(2)无感染、酮症酸中毒、高渗性非酮症糖尿病昏迷、低血糖症等急性并发症;
(3)合并原发性及其它继发性肾脏病者;
(4)合并严重消化、循环、造血等系统原发性疾病者;
(5)严重的精神疾病(经精神科医生会诊)或因其它原因不能配合调查者。
监测项目:每二周监测症状、舌脉、血压、餐后2h毛细血管血糖,试验前后各监测尿24h微量白蛋白定量,血清肌酐(SCr)、低密度脂蛋白(LDL-C)、血胆固醇(TCH)、甘油三酯(TG)、血栓调节蛋白(TM)。
疗程:12周。
治疗方案:
(1)基础治疗:
①糖尿病健康教育、体育锻炼及低盐优质蛋白糖尿病饮食:每日食盐摄入量≤6克,精蛋白摄入量:0.8g/Kg·d;
②控制血压:目标:＜130/80mmHg;可应用非ACEI及ARB外的所有降压药;
③控制血糖:目标:FPG≤7.0mmol/L 2hPG≤10.0mmol/L全部应用糖适平和/或胰岛素治疗;
④对症处理。
(2)分组治疗:
T组:三芪口服液:1支/次,3次/日,口服;
L组:洛汀新片:10mg/次,1次/日,口服。
调查方法:
(1)药物洗脱:共2周,停用所有ACEI、ARB、益气活血类中药等制剂;给予受试者DM教育,低盐低脂优质低蛋白饮食;血压控制于＜130/80mmHg水平;血糖控制在FPG≤7.0mmol/L,2hPG≤10.0mmol/L水平;结束复查24h尿微量白蛋白定量及排泄率、血浆TM、低密度脂蛋白(LDL-C)、TCH、TG水平;
(2)分组:将合格病例分为洛汀新组(L组)及三芪组(T组);
(3)试验过程依从性:采用药物记量的方法了解患者依从性。耐心向患者做好解释工作,使其充分理解,配合研究。
(4)干扰和沾染的控制:所有病人受试期间不得接受试验措施以外的相关药物或治疗,尽量保证病人按照治疗方案规定用药,而不受其他药物等治疗措施的影响。
结果:
(1)治疗前两组患者一般情况、24h尿微量白蛋白定量、肾功能、血栓调节蛋白等,差异无统计学意义(P＞0.05);治疗过程中,两组患者血糖差异无统计学意义(P＞0.05);
(2)治疗后T组DN患者24h尿微量白蛋白定量、血栓调节蛋白、低密度脂蛋白、症状积分较治疗前明显降低,差异有显著性统计学意义(P＜0.01);
(3)治疗后T组与L组比较:T组症状积分前后差值高于L组,差异有显著性统计学意义(P＜0.01);T组LDL-C治疗前后与L组比较,明显降低,差异有统计学意义(P＜0.05)。24h尿微量白蛋白定量、血栓调节蛋白等差异无统计学意义(P＞0.05)。
二、实验部分:
实验一:三芪口服液对实验性糖尿病肾病模型大鼠肾组织AGEs/RAGE、PAI-1、TGF-β1表达影响的研究。
选鼠分组:选用SD雄性大鼠,设立正常对照组(C组);余动物采用STZ单次腹腔注射方法制备糖尿病(DM)动物模型。
DN模型制备及分组:DM大鼠模型成功后,给予隔日高脂饲料饲养4周,DN大鼠模型成功,随机分为M组、T组。
干预起始点:DN模型成功,分组后即开始干预。
干预方式:①饲料:T、M组给予隔日高脂饲料,C组给予普通饲料;实验期间均自由进食和饮水;②药物:T组给予三芪口服液灌胃,C及M组给予生理盐水灌胃。
干预时限:6周。
大鼠淘汰标准:①干预过程中,测定血糖值＜16.8mmol/L者,予以淘汰;②6周后处死大鼠,光镜示肾组织无明显病变者,予以淘汰。
标本制备:选择DN模型制备及分组干预后C组、M组、T组大鼠肾组织,每组随机选择6例标本。
实验方法:免疫组化法。
观察项目:测定肾组织AGEs/RAGE、TGF-β_1、PAI—1等的免疫组化染色面积、面密度及积分光密度。
实验二:三芪口服液对糖尿病大鼠肾足细胞及其膜蛋白PCX、nephrin表达的影响。
标本来源、实验方法同实验一。
观察项目:测定肾组织足细胞计数、PCX荧光染色面积,Nephrin、PCX面密度及积分光密度。
结果:
实验一:三芪口服液对实验性糖尿病肾病模型大鼠肾组织AGEs/RAGE、PAI-1、TGF-β1表达影响的研究。
24h蛋白尿定量及排泄率:
(1)T、M组24h尿蛋白定量、排泄率较C组升高,差异有显著性统计学意义(P＜0.01);
(2)T组24h尿蛋白定量、排泄率较M组降低,差异有显著性统计学意义(P＜0.01)。
血尿素氮、肌酐:
C、T、M组间比较差异无统计学意义(P＞0.05)。
总胆固醇、甘油三脂、低密度脂蛋白:
(1)T、M组TCh、TG较C组均升高,差异有显著性统计学意义(P＜0.01);
(2)T组TCh、TG较M组降低,差异有统计学意义(P＜0.05或P＜0.01)。
AGEs:在肾小球、肾小管、毛细血管、系膜等肾组织均有AGEs阳性物质存在,胞浆和细胞外基质均有AGEs沉积。和C组比较,M组呈强阳性表达;T组染色面积及积分光密度均较M组降低,差异有显著性统计学意义(P＜0.01)。
RAGE:主要表达定位在肾小球,和C组比较,在M组表达明显增加;T组染色面积及积分光密度均较M组明显减弱,差异有显著性统计学意义(P＜0.05)。
TGF-β_1:主要定位在肾小管及间质处,肾小球表达较弱;T组免疫组化染色面密度及积分光密度均较M组降低,差异有显著性,差异有显著性统计学意义(P＜0.01)。
PAI-1:主要表达定位于肾小管、收集管,小球内无表达,和C组比较,M组呈强阳性表达;T组染色面积及积分光密度均较M组降低,差异有统计学意义(P＜0.05)。
实验二:三芪口服液对糖尿病肾病大鼠肾足细胞及其膜蛋白PCX、nephrin表达的影响。
肾小球足细胞计数:
与C组相比,M组肾小球足细胞数明显下降,(P＜0.05),T组肾小球足细胞数亦有下降,但较M组足细胞数为多,结果分析统计有显著差异(P＜0.05)。
肾小球足细胞标志性蛋白PCX平均荧光密度:
C、M和T组三组肾脏肾小球足细胞PCX荧光密度比较NC组可见PCX阳性信号沿肾小球血管壁走行分布均匀、连续;M组PCX阳性信号分布不均匀,而且不连续;T组PCX阳性信号较M组分布均匀,较M组连续。定量分析结果显示,M组PCX平均荧光密度均低于C、T组(分别降低了48.5%、30.1%)(分别为P＜0.001,P＜0.05)。
肾小球nephrin蛋白表达:
M组大鼠肾小球nephrin蛋白表达显著低于C组(P＜0.05);T组大鼠肾小球nephrin蛋白表达显著高于M组(P＜0.05);T组与C组比较,肾小球nephrin蛋白表达无显著差异(P＞0.05);C组大鼠肾脏nephrin蛋白在肾小球沿毛细血管袢呈线状分布;M组大鼠部分肾小球中nephrin蛋白呈颗粒状分布,三芪口服液治疗能显著抑制DN大鼠肾小球nephrin蛋白的重新分布。
肾小球足细胞分析指标与24小时尿蛋白相关性:
Pearson相关分析结果显示,24小时UMA与肾小球足细胞PCX平均荧光密度、nephrin蛋白表达呈负相关(P＜0.01)。
结论:
1.三芪口服液能改善早中期DN患者临床症状、蛋白尿、降低血浆TM水平,稳定肾功能,干预过程中未发现其它不良反应,结果提示可将血栓调节蛋白升高作为干预DN的起点。
2.益气活血中药复方三芪口服液对DN肾脏保护作用的机制可能是:抑制AGEs/RAGE系统的表达,从而下调肾组织TGF-β_1的表达、减少PAI-1生成,减轻ECM积聚,从而调节细胞、细胞外基质、细胞因子和生长因子间的网络调控,延缓DN肾间质纤维化及肾小球硬化的进展。
3.益气活血中药复方三芪口服液能够上调肾足细胞裂孔隔膜nephrin、足细胞特异性标志蛋白PCX的蛋白表达,从而改善足细胞的损伤,改善肾脏足细胞的超微结构,减少尿蛋白,延缓DN进程。
Background
Recently,the prevalence rate of diabetes is rising unceasingly in our country.Along with insulin widespread application,the mortality rate of Diabetes' acute complication,such as ketoacidosis,are obviously dropped,and the chronic complication such as diabetic nephropathy has become one of most common complications with diabetic life extension.In clinical practice,diabetes nephrosis is often divided into 3 stages,namely:morning stage,intermediate stage and advanced stage.In different stage,the emphasis of treatment is also different.
Professor Yang consider that the Deficiency of Qi and the Blood Stasis is the mainly etiopathogenesis of diabetic nephropathy,especially when disease is morning or intermediate stage,so the therapeutic rule- "benefiting vital energy and promoting blood flow" can applied in the treatment of diabetic nephropathy;when their stage are morning or intermediate,the effective treatment is the key of pathogenetic condition reverse.So we study the mechanism of action of SanQi Oral Solution to the diabetic nephropathy by the methods of pharmacodynamics and morphology,in order to provide the substantial theory and plenitudinous scientic evidence for SanQi Oral Solution which is composed according to benefiting vital energy and promoting blood flow method cure diabetic nephropathy.
Objective.
To explore the effect and mechanism of SanQi Oral Solution in the defence and treatment of morning diabetic nephropathy,and found SanQi Oral Solution' s function superiority stage.
Methods:
1).Clinical study:
This part of the study is controlled.According to degree of microalbuminuria and general condition,58 patients suffered from morning stage diabetic nephropathy were divided into treatment and control group. There was no statistically significant difference between two groups in sex, age,severity of the disease and laboratory items.The patients of the treatment group received management of SanQi Oral Solution while the patients of the control group took the drug of Lotensin.The course of treatment lasted for 12 weeks,during which the changes of clinical findings and lab index were monitored and recorded,including renal function,microalbuminuria,blood fat, blood pressure,blood glucose,thrombomodulin and clinical symptoms and signs. The differences between the symptom index before and after treatment were then calculated and tested,as well as the microalbuminuria of 24 hours and thrombomodulin.
2).Experimental Study:
(1) PartⅠ.Study of effects of the SanQi oral solution on the expression of AGEs and its acceptor,as well as regulation factor
42 SD male adult rats of specified-pathogen free were injected with streptozotocin(STZ) intraperitoneally to prepare for Diabetes Mellitus animal model and then randomly divided into 3 groups including model group(M group),SanQi Oral Solution group(S group) after diabetes was induced successfully.Another group was set for experiment control,consisted of normal SD rats.After diabetes was induced successfully,the rats of diabetes animal model were continually raised with high fat food every other day for another 4 weeks in order to induce the diabetes nephropathy in them.After 6 weeks of drugs treatments or placebo managements,all the animals were put to death and their kidneys were removed for the pathological study.6 renal samples were randomly obtained from the rats of group C,M,and T in PartⅡstudy,respectively.Expression of AGEs/RAGE,PAI-1 and TGF-β1 were detected by immunohistochemistry.The stained area,area density,and photodensity were then observed and recorded.
(2) PartⅡ.Study of effects of the SanQi oral solution on the DN rats' podocyte as well as the expression of the PCX and Nephrin.
6 renal samples were randomly obtained from the rats of group C,M,and T in PartⅠstudy,respectively.Expression of PCX and Nephrin were detected by immunohistochemistry.The methord is the same as PartⅠ.
Results:
1).Clinical study.
(a).there' s no statistical significant difference in the general condition of the patients,the urinary protein of 24 hours,and renal function before treatment,No statistical significance was found in the difference of blood pressure,values of blood glucose during the course of treatment.
(b).As to the patients of T group,the symptomatic scores,TM and microalbuminuria of 24 hours after treatment decreased obviously compared to that before the treatment,with statistical significance(P＜0.01).
(c).There were no statistical significance found in the difference of changes of urinary protein after treatment between the T group and L group (P＞0.05).However,the changes of symptomatic scores in T group was higher than that of L group after treatment with statistical significance(P＜0.01).
2) Experimental Study:
(1).Study of effects of the SanQi oral solution on the expression of AGEs and its acceptor,as well as regulation factor.
a.microalbuminuria of 24 hours,urinary protein in T,and M group increased with statistical significance,compared to that of C group(P＜0.01).Excretion of urinary protein in 24 hours in T group decreased statistically significantly, in contrast to that of M group(P＜0.01).
b.Changes of values of blood urea nitrogen and serum creatinine.There' s no statistical significant difference demonstrated between C,T,and M group
c.The cholesterol total(TCh),low density lipoprotein-oholesterol (LDL-C)and glycerol total(TG) fluctuation.The mean values of TCh and TG in T,and M group increased statistically significantly,compared that of C group(P＜0.01).In T group,the values of TCh,LDL-C and TG decreased with statistical significance,compared to that of M group(P＜0.01).
d.Expression of AGEs.The AGEs was located in the glomerulus,kidney tubules,capillaries,mesenteria and etc.And deposited at the kytoplasm and Extracellular Martix.Strong positive expression was found in group M. According to the outcomes of immunohistology,the values of area density and photodensity of positively stained area were less than that of M group with statistical significance(P＜0.01).
e.Expression of RAGE.The expression of RAGE was located mainly in glomerulus.It' s more strongly expressed in group M than in C group.The value of area density and photodensity in M group positively stained area were higher than that of T group(P＜0.01).
f.Expression of PAI-1.Expression of PAI-1 was located in renal tubule and collecting pipe but no expression located in glomerulus.It' s stronger positively expressed in M group than in C.The values of area density and photodensity of PAI-1 positively stained area in group T were lower than that of group M with statistical significance(p＜0.05).
g.Expression of TGF-β1.Expression of TGF-β1.was located in the renal tubule and interstitium.It' s weakly expressed in the glomerulus.It' s lower for the value of area density and photodensity in group T than that of group M with statistical significance(P＜0.01).
(2)Study of effects of the SanQi oral solution on the DN rats' podocyte as well as the expression of the PCX and Nephrin.
a.Glomerulus foot cell count:
Compared with the C group,M group glomerular podocyte number decreased obviously.(P＜0.05).T Group glomerular podocyte number also dropped,but cells is more than the M group,the results of statistical analysis different significantly(P＜0.05)
b.Expression of PCX:
NC Group PCX-positive signal can be seen along the glomerular vessel wall distribution running continuously;M Group PCX distribute not only uneven signals,but also incontinuous;Compared with the M group,T PCX-positive group signals distributed continuously and uniformly.Quantitative analysis revealed that,M Group PCX mean fluorescence density were lower than C,T group (48.5%lower,respectively,30.1%)(respectively P＜0.001,P＜0.05).
c.Expression of Nephrin
M Group glomerular nephrin protein expression was significantly lower than C group(P＜0.05);T Group glomerular nephrin protein expression was significantly higher than M group(P＜0.05);T group compared with C group, the expression of nephrin protein has no significant difference(P＞0.05).
d.Analysis of glomerular podocyte indicators with a 24-hour urine protein relevance:
Analysis of results showed that the negative correlation exist among thd 24h UMA,expression of PCX and nephrin.(P＜0.01) Conclusion
(1).SanQi Oral Solution can improve the patients' clinical symptoms and renal function,decrease the urine protein,and the level of TM,stable renal function,results suggest that SanQi Oral Solution may be used to treat DN as soon as Thrombomodulin increased.
(2).The mechanism that SanQi Oral Solution ameliorated the structure and function damage of DN model rats may be due to inhibition of AGEs/RAGE,down-regulation of the expression of TGF-β1,increase of degeneration of PAI-1,reduction of extracellular matrix accumulation,and amelioration of renal pathological lesions.These therapeutic effects may improve renal hypertrophy,regulation of cells,ECM,cytokines,and growth factors resulting in delayed progress of DN.
(3).SanQi oral liquid medicine can up-regulate kidney podocyte nephrin, podocyte-specific marker proteins of the protein expression PCX so as to improve podocyte damage,improve podocyte ultrastructure of the kidney to reduce urinary protein,delay DN process.
探讨益气活血中药复方三芪口服液干预糖尿病肾病的起始点及肾保护作用机制研究。
方法:
临床部分:
病例来源:广东省中医院大学城医院的住院及门诊病人共58例。
诊断标准:
(1)西医诊断标准:
①糖尿病诊断标准:参照1999年WHO标准。
②糖尿病肾病分期标准:参照Mogensen标准及王海燕《肾脏病学》。
Ⅰ期:肾脏肥大和肾小球高滤过,此期肾脏结构正常。
Ⅱ期:运动后出现微量白蛋白尿,肾脏病理示肾小球毛细血管基底膜(GBM)增厚。
Ⅲ期:持续性微量白蛋白尿,尿白蛋白排泄率(UAER)在20～200μg/min或30～300mg/24h之间,肾脏病理示肾小球系膜基质增加及GBM明显增厚,又称早期糖尿病肾病或亚临床糖尿病肾病。
Ⅳ期:UAER＞200ug/min或持续尿蛋白＞500mg/24h,病理示肾小球系膜基质明显增加及GBM明显增厚,部分小球荒废,又称临床期糖尿病肾病或中期糖尿病肾病。
Ⅴ期:肾功能破坏,肾小球荒废,又称终末期糖尿病肾病。
(2)中医证型诊断标准:
参照2002年版《中药新药临床研究指导原则》中关于气虚证及血瘀证的辨证标准。
(3)症状积分标准:
症状按无、轻、中、重记0、1、2、3分,舌脉记“有”为1分,“无”为0分。
纳入标准:
(1)符合以上中西医诊断标准;
(2)血糖:FPG≤7.0mmol/L 2HPG≤10.0mmol/L,病情稳定二周以上;
(3)蛋白尿:24h尿蛋白定量≤0.3g,UAER＜200ug/min。
同时具备以上三条方可纳入临床试验。
排除标准:
(1)排除其它原发及继发性原因所致蛋白尿;
(2)无感染、酮症酸中毒、高渗性非酮症糖尿病昏迷、低血糖症等急性并发症;
(3)合并原发性及其它继发性肾脏病者;
(4)合并严重消化、循环、造血等系统原发性疾病者;
(5)严重的精神疾病(经精神科医生会诊)或因其它原因不能配合调查者。
监测项目:每二周监测症状、舌脉、血压、餐后2h毛细血管血糖,试验前后各监测尿24h微量白蛋白定量,血清肌酐(SCr)、低密度脂蛋白(LDL-C)、血胆固醇(TCH)、甘油三酯(TG)、血栓调节蛋白(TM)。
疗程:12周。
治疗方案:
(1)基础治疗:
①糖尿病健康教育、体育锻炼及低盐优质蛋白糖尿病饮食:每日食盐摄入量≤6克,精蛋白摄入量:0.8g/Kg·d;
②控制血压:目标:＜130/80mmHg;可应用非ACEI及ARB外的所有降压药;
③控制血糖:目标:FPG≤7.0mmol/L 2hPG≤10.0mmol/L全部应用糖适平和/或胰岛素治疗;
④对症处理。
(2)分组治疗:
T组:三芪口服液:1支/次,3次/日,口服;
L组:洛汀新片:10mg/次,1次/日,口服。
调查方法:
(1)药物洗脱:共2周,停用所有ACEI、ARB、益气活血类中药等制剂;给予受试者DM教育,低盐低脂优质低蛋白饮食;血压控制于＜130/80mmHg水平;血糖控制在FPG≤7.0mmol/L,2hPG≤10.0mmol/L水平;结束复查24h尿微量白蛋白定量及排泄率、血浆TM、低密度脂蛋白(LDL-C)、TCH、TG水平;
(2)分组:将合格病例分为洛汀新组(L组)及三芪组(T组);
(3)试验过程依从性:采用药物记量的方法了解患者依从性。耐心向患者做好解释工作,使其充分理解,配合研究。
(4)干扰和沾染的控制:所有病人受试期间不得接受试验措施以外的相关药物或治疗,尽量保证病人按照治疗方案规定用药,而不受其他药物等治疗措施的影响。
结果:
(1)治疗前两组患者一般情况、24h尿微量白蛋白定量、肾功能、血栓调节蛋白等,差异无统计学意义(P＞0.05);治疗过程中,两组患者血糖差异无统计学意义(P＞0.05);
(2)治疗后T组DN患者24h尿微量白蛋白定量、血栓调节蛋白、低密度脂蛋白、症状积分较治疗前明显降低,差异有显著性统计学意义(P＜0.01);
(3)治疗后T组与L组比较:T组症状积分前后差值高于L组,差异有显著性统计学意义(P＜0.01);T组LDL-C治疗前后与L组比较,明显降低,差异有统计学意义(P＜0.05)。24h尿微量白蛋白定量、血栓调节蛋白等差异无统计学意义(P＞0.05)。
二、实验部分:
实验一:三芪口服液对实验性糖尿病肾病模型大鼠肾组织AGEs/RAGE、PAI-1、TGF-β1表达影响的研究。
选鼠分组:选用SD雄性大鼠,设立正常对照组(C组);余动物采用STZ单次腹腔注射方法制备糖尿病(DM)动物模型。
DN模型制备及分组:DM大鼠模型成功后,给予隔日高脂饲料饲养4周,DN大鼠模型成功,随机分为M组、T组。
干预起始点:DN模型成功,分组后即开始干预。
干预方式:①饲料:T、M组给予隔日高脂饲料,C组给予普通饲料;实验期间均自由进食和饮水;②药物:T组给予三芪口服液灌胃,C及M组给予生理盐水灌胃。
干预时限:6周。
大鼠淘汰标准:①干预过程中,测定血糖值＜16.8mmol/L者,予以淘汰;②6周后处死大鼠,光镜示肾组织无明显病变者,予以淘汰。
标本制备:选择DN模型制备及分组干预后C组、M组、T组大鼠肾组织,每组随机选择6例标本。
实验方法:免疫组化法。
观察项目:测定肾组织AGEs/RAGE、TGF-β_1、PAI—1等的免疫组化染色面积、面密度及积分光密度。
实验二:三芪口服液对糖尿病大鼠肾足细胞及其膜蛋白PCX、nephrin表达的影响。
标本来源、实验方法同实验一。
观察项目:测定肾组织足细胞计数、PCX荧光染色面积,Nephrin、PCX面密度及积分光密度。
结果:
实验一:三芪口服液对实验性糖尿病肾病模型大鼠肾组织AGEs/RAGE、PAI-1、TGF-β1表达影响的研究。
24h蛋白尿定量及排泄率:
(1)T、M组24h尿蛋白定量、排泄率较C组升高,差异有显著性统计学意义(P＜0.01);
(2)T组24h尿蛋白定量、排泄率较M组降低,差异有显著性统计学意义(P＜0.01)。
血尿素氮、肌酐:
C、T、M组间比较差异无统计学意义(P＞0.05)。
总胆固醇、甘油三脂、低密度脂蛋白:
(1)T、M组TCh、TG较C组均升高,差异有显著性统计学意义(P＜0.01);
(2)T组TCh、TG较M组降低,差异有统计学意义(P＜0.05或P＜0.01)。
AGEs:在肾小球、肾小管、毛细血管、系膜等肾组织均有AGEs阳性物质存在,胞浆和细胞外基质均有AGEs沉积。和C组比较,M组呈强阳性表达;T组染色面积及积分光密度均较M组降低,差异有显著性统计学意义(P＜0.01)。
RAGE:主要表达定位在肾小球,和C组比较,在M组表达明显增加;T组染色面积及积分光密度均较M组明显减弱,差异有显著性统计学意义(P＜0.05)。
TGF-β_1:主要定位在肾小管及间质处,肾小球表达较弱;T组免疫组化染色面密度及积分光密度均较M组降低,差异有显著性,差异有显著性统计学意义(P＜0.01)。
PAI-1:主要表达定位于肾小管、收集管,小球内无表达,和C组比较,M组呈强阳性表达;T组染色面积及积分光密度均较M组降低,差异有统计学意义(P＜0.05)。
实验二:三芪口服液对糖尿病肾病大鼠肾足细胞及其膜蛋白PCX、nephrin表达的影响。
肾小球足细胞计数:
与C组相比,M组肾小球足细胞数明显下降,(P＜0.05),T组肾小球足细胞数亦有下降,但较M组足细胞数为多,结果分析统计有显著差异(P＜0.05)。
肾小球足细胞标志性蛋白PCX平均荧光密度:
C、M和T组三组肾脏肾小球足细胞PCX荧光密度比较NC组可见PCX阳性信号沿肾小球血管壁走行分布均匀、连续;M组PCX阳性信号分布不均匀,而且不连续;T组PCX阳性信号较M组分布均匀,较M组连续。定量分析结果显示,M组PCX平均荧光密度均低于C、T组(分别降低了48.5%、30.1%)(分别为P＜0.001,P＜0.05)。
肾小球nephrin蛋白表达:
M组大鼠肾小球nephrin蛋白表达显著低于C组(P＜0.05);T组大鼠肾小球nephrin蛋白表达显著高于M组(P＜0.05);T组与C组比较,肾小球nephrin蛋白表达无显著差异(P＞0.05);C组大鼠肾脏nephrin蛋白在肾小球沿毛细血管袢呈线状分布;M组大鼠部分肾小球中nephrin蛋白呈颗粒状分布,三芪口服液治疗能显著抑制DN大鼠肾小球nephrin蛋白的重新分布。
肾小球足细胞分析指标与24小时尿蛋白相关性:
Pearson相关分析结果显示,24小时UMA与肾小球足细胞PCX平均荧光密度、nephrin蛋白表达呈负相关(P＜0.01)。
结论:
1.三芪口服液能改善早中期DN患者临床症状、蛋白尿、降低血浆TM水平,稳定肾功能,干预过程中未发现其它不良反应,结果提示可将血栓调节蛋白升高作为干预DN的起点。
2.益气活血中药复方三芪口服液对DN肾脏保护作用的机制可能是:抑制AGEs/RAGE系统的表达,从而下调肾组织TGF-β_1的表达、减少PAI-1生成,减轻ECM积聚,从而调节细胞、细胞外基质、细胞因子和生长因子间的网络调控,延缓DN肾间质纤维化及肾小球硬化的进展。
3.益气活血中药复方三芪口服液能够上调肾足细胞裂孔隔膜nephrin、足细胞特异性标志蛋白PCX的蛋白表达,从而改善足细胞的损伤,改善肾脏足细胞的超微结构,减少尿蛋白,延缓DN进程。
Background
Recently,the prevalence rate of diabetes is rising unceasingly in our country.Along with insulin widespread application,the mortality rate of Diabetes' acute complication,such as ketoacidosis,are obviously dropped,and the chronic complication such as diabetic nephropathy has become one of most common complications with diabetic life extension.In clinical practice,diabetes nephrosis is often divided into 3 stages,namely:morning stage,intermediate stage and advanced stage.In different stage,the emphasis of treatment is also different.
Professor Yang consider that the Deficiency of Qi and the Blood Stasis is the mainly etiopathogenesis of diabetic nephropathy,especially when disease is morning or intermediate stage,so the therapeutic rule- "benefiting vital energy and promoting blood flow" can applied in the treatment of diabetic nephropathy;when their stage are morning or intermediate,the effective treatment is the key of pathogenetic condition reverse.So we study the mechanism of action of SanQi Oral Solution to the diabetic nephropathy by the methods of pharmacodynamics and morphology,in order to provide the substantial theory and plenitudinous scientic evidence for SanQi Oral Solution which is composed according to benefiting vital energy and promoting blood flow method cure diabetic nephropathy.
Objective.
To explore the effect and mechanism of SanQi Oral Solution in the defence and treatment of morning diabetic nephropathy,and found SanQi Oral Solution' s function superiority stage.
Methods:
1).Clinical study:
This part of the study is controlled.According to degree of microalbuminuria and general condition,58 patients suffered from morning stage diabetic nephropathy were divided into treatment and control group. There was no statistically significant difference between two groups in sex, age,severity of the disease and laboratory items.The patients of the treatment group received management of SanQi Oral Solution while the patients of the control group took the drug of Lotensin.The course of treatment lasted for 12 weeks,during which the changes of clinical findings and lab index were monitored and recorded,including renal function,microalbuminuria,blood fat, blood pressure,blood glucose,thrombomodulin and clinical symptoms and signs. The differences between the symptom index before and after treatment were then calculated and tested,as well as the microalbuminuria of 24 hours and thrombomodulin.
2).Experimental Study:
(1) PartⅠ.Study of effects of the SanQi oral solution on the expression of AGEs and its acceptor,as well as regulation factor
42 SD male adult rats of specified-pathogen free were injected with streptozotocin(STZ) intraperitoneally to prepare for Diabetes Mellitus animal model and then randomly divided into 3 groups including model group(M group),SanQi Oral Solution group(S group) after diabetes was induced successfully.Another group was set for experiment control,consisted of normal SD rats.After diabetes was induced successfully,the rats of diabetes animal model were continually raised with high fat food every other day for another 4 weeks in order to induce the diabetes nephropathy in them.After 6 weeks of drugs treatments or placebo managements,all the animals were put to death and their kidneys were removed for the pathological study.6 renal samples were randomly obtained from the rats of group C,M,and T in PartⅡstudy,respectively.Expression of AGEs/RAGE,PAI-1 and TGF-β1 were detected by immunohistochemistry.The stained area,area density,and photodensity were then observed and recorded.
(2) PartⅡ.Study of effects of the SanQi oral solution on the DN rats' podocyte as well as the expression of the PCX and Nephrin.
6 renal samples were randomly obtained from the rats of group C,M,and T in PartⅠstudy,respectively.Expression of PCX and Nephrin were detected by immunohistochemistry.The methord is the same as PartⅠ.
Results:
1).Clinical study.
(a).there' s no statistical significant difference in the general condition of the patients,the urinary protein of 24 hours,and renal function before treatment,No statistical significance was found in the difference of blood pressure,values of blood glucose during the course of treatment.
(b).As to the patients of T group,the symptomatic scores,TM and microalbuminuria of 24 hours after treatment decreased obviously compared to that before the treatment,with statistical significance(P＜0.01).
(c).There were no statistical significance found in the difference of changes of urinary protein after treatment between the T group and L group (P＞0.05).However,the changes of symptomatic scores in T group was higher than that of L group after treatment with statistical significance(P＜0.01).
2) Experimental Study:
(1).Study of effects of the SanQi oral solution on the expression of AGEs and its acceptor,as well as regulation factor.
a.microalbuminuria of 24 hours,urinary protein in T,and M group increased with statistical significance,compared to that of C group(P＜0.01).Excretion of urinary protein in 24 hours in T group decreased statistically significantly, in contrast to that of M group(P＜0.01).
b.Changes of values of blood urea nitrogen and serum creatinine.There' s no statistical significant difference demonstrated between C,T,and M group
c.The cholesterol total(TCh),low density lipoprotein-oholesterol (LDL-C)and glycerol total(TG) fluctuation.The mean values of TCh and TG in T,and M group increased statistically significantly,compared that of C group(P＜0.01).In T group,the values of TCh,LDL-C and TG decreased with statistical significance,compared to that of M group(P＜0.01).
d.Expression of AGEs.The AGEs was located in the glomerulus,kidney tubules,capillaries,mesenteria and etc.And deposited at the kytoplasm and Extracellular Martix.Strong positive expression was found in group M. According to the outcomes of immunohistology,the values of area density and photodensity of positively stained area were less than that of M group with statistical significance(P＜0.01).
e.Expression of RAGE.The expression of RAGE was located mainly in glomerulus.It' s more strongly expressed in group M than in C group.The value of area density and photodensity in M group positively stained area were higher than that of T group(P＜0.01).
f.Expression of PAI-1.Expression of PAI-1 was located in renal tubule and collecting pipe but no expression located in glomerulus.It' s stronger positively expressed in M group than in C.The values of area density and photodensity of PAI-1 positively stained area in group T were lower than that of group M with statistical significance(p＜0.05).
g.Expression of TGF-β1.Expression of TGF-β1.was located in the renal tubule and interstitium.It' s weakly expressed in the glomerulus.It' s lower for the value of area density and photodensity in group T than that of group M with statistical significance(P＜0.01).
(2)Study of effects of the SanQi oral solution on the DN rats' podocyte as well as the expression of the PCX and Nephrin.
a.Glomerulus foot cell count:
Compared with the C group,M group glomerular podocyte number decreased obviously.(P＜0.05).T Group glomerular podocyte number also dropped,but cells is more than the M group,the results of statistical analysis different significantly(P＜0.05)
b.Expression of PCX:
NC Group PCX-positive signal can be seen along the glomerular vessel wall distribution running continuously;M Group PCX distribute not only uneven signals,but also incontinuous;Compared with the M group,T PCX-positive group signals distributed continuously and uniformly.Quantitative analysis revealed that,M Group PCX mean fluorescence density were lower than C,T group (48.5%lower,respectively,30.1%)(respectively P＜0.001,P＜0.05).
c.Expression of Nephrin
M Group glomerular nephrin protein expression was significantly lower than C group(P＜0.05);T Group glomerular nephrin protein expression was significantly higher than M group(P＜0.05);T group compared with C group, the expression of nephrin protein has no significant difference(P＞0.05).
d.Analysis of glomerular podocyte indicators with a 24-hour urine protein relevance:
Analysis of results showed that the negative correlation exist among thd 24h UMA,expression of PCX and nephrin.(P＜0.01) Conclusion
(1).SanQi Oral Solution can improve the patients' clinical symptoms and renal function,decrease the urine protein,and the level of TM,stable renal function,results suggest that SanQi Oral Solution may be used to treat DN as soon as Thrombomodulin increased.
(2).The mechanism that SanQi Oral Solution ameliorated the structure and function damage of DN model rats may be due to inhibition of AGEs/RAGE,down-regulation of the expression of TGF-β1,increase of degeneration of PAI-1,reduction of extracellular matrix accumulation,and amelioration of renal pathological lesions.These therapeutic effects may improve renal hypertrophy,regulation of cells,ECM,cytokines,and growth factors resulting in delayed progress of DN.
(3).SanQi oral liquid medicine can up-regulate kidney podocyte nephrin, podocyte-specific marker proteins of the protein expression PCX so as to improve podocyte damage,improve podocyte ultrastructure of the kidney to reduce urinary protein,delay DN process.
引文
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