尿毒清颗粒对慢性肾功能衰竭药理作用的分子机制
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摘要
慢性肾功能衰竭(Chronic Renal Failure, CRF)见于各种慢性肾脏疾病的晚期,为各种原发和继发性慢性肾脏疾病持续发展的共同转归。发病率大约万分之一,死亡率高达67.6%,占人群死亡率的10%,只有20%的患者在排除可逆因素后获得缓解。当患者进入慢性肾功能衰竭终末期(尿毒症)阶段后,治疗棘手,全身各系统都会受损,严重危害人类的健康和生命。西药治疗常采用血管紧张素转换酶抑制剂(ACEIs)和血管紧张素受体拮抗剂(ARBs),但这两种药物只能达到缓解慢性肾功能衰竭的作用,而无法阻断慢性肾功能衰竭的进程；随着技术的发展出现了透析和移植两个肾脏替代治疗方式,但是价格昂贵,供肾不足等因素又限制了其应用。因此,探求中医疗法是一条重要途径。尿毒清颗粒(Uremic Clearance Granule)主要用于慢性肾功能衰竭氮质血症期和尿毒症早期、中医辨证属脾虚湿浊症和脾虚血瘀症者的治疗,已有十余年的临床应用历史,但大多数研究属于临床疗效观察,对于作用机理方面的研究较少,动物实验研究尚缺乏深度,为了使其得到广泛的推广应用,利用现代科学技术手段与多学科方法研究该方的有效成分和作用机理就成了当务之急。
本论文以腺嘌呤饲喂法建立的慢性肾功能衰竭Wistar大鼠模型为实验材料,采用分子生物学的方法从DNA甲基化修饰、关键基因的mRNA及蛋白表达,以及疾病相关代谢产物三个层次系统地研究了尿毒清颗粒对慢性肾功能衰竭治疗的分子机制,研究结果为尿毒清颗粒在临床治疗上的应用提供了理论依据。主要结果如下：
1.通过本研究发现尿毒清颗粒可以在mRNA和蛋白质水平减少转化生长因子-β1 (TGF-β1)的表达。TGF-β1是引起肾小球硬化的主要介质,以其为靶向的治疗已成为近年来的研究热点。我们用SYBR Green实时荧光定量PCR技术检测了正常对照组大鼠、病理对照组大鼠和经尿毒清治疗后大鼠肾皮质TGF-β1及其下游基因mRNA的表达。为了确证TGF-β1 mRNA在本实验中表达升高是否引起了TGF-β1蛋白表达的增多,我们用免疫组织化学技术检测了大鼠肾皮质TGF-β1蛋白的表达。为了进一步研究各实验组TGF-β1表达变化出现的原因,我们用甲基化特异性PCR技术检测单基因TGF-β1启动子甲基化状态的变化,发现慢性肾功能衰竭大鼠TGF-β1启动子有些位点出现了去甲基化现象,而尿毒清颗粒治疗组该位点甲基化状态得到恢复。结果表明尿毒清颗粒对慢性肾功能衰竭的治疗是通过下调以TGF-β1为中心的多基因表达来进行的。
2.生化试验研究发现尿毒清颗粒可以降低慢性肾功能衰竭大鼠血清中同型半胱氨酸浓度,减轻高同型半胱氨酸血症。慢性肾功能衰竭患者血清同型半胱氨酸水平升高发生率高达82.5%,其水平为正常人的2-3倍。高同型半胱氨酸可能通过损害血管内皮,刺激血管平滑肌增殖等原因在慢性肾功能衰竭发病机制中起重要作用。我们用高效液相色谱检测了正常组对照大鼠、病理对照组大鼠和经尿毒清治疗后大鼠血清中同型半胱氨酸的含量,发现与病理对照组相比,经尿毒清治疗的大鼠血清同型半胱氨酸浓度显著下降。此结果揭示了尿毒清颗粒可以通过提高对同型半胱氨酸的清除达到恢复慢性肾功能衰竭大鼠肾功能的作用。
3.DNA甲基化研究发现尿毒清颗粒可以使慢性肾功能衰竭大鼠基因组DNA从低甲基化状态恢复到正常水平。同型半胱氨酸的积累会导致体内DNA甲基化异常,本实验对各组大鼠肾皮质基因组DNA甲基化状态进行甲基化敏感扩增多态性分析,结果发现慢性肾功能衰竭大鼠肾皮质基因组DNA出现了低甲基化现象,尿毒清颗粒治疗可以使其恢复为正常水平。结果揭示尿毒清颗粒可以通过表观遗传机制调节基因组DNA的甲基化状态来对慢性肾功能衰竭进行治疗。
上述研究结果表明：尿毒清颗粒能明显改善腺嘿吟诱导的慢性肾功能衰竭大鼠的肾功能,在mRNA和蛋白水平下调TGF-β1的表达,并通过对同型半胱氨酸的清除,缓解高同型半胱氦酸血症,改变慢性肾功能衰竭大鼠的去甲基化状态关闭TGF-β1基因的表达,通过多成分协作达到治疗作用。
Chronic Renal Failure (CRF) is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which is a progressive loss of renal function over a period of months or years. There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. The number of patients with end-stage renal disease (ESRD) has increased rapidly over the last three decades, and prior to the advent of renal replacement therapy (dialysis and transplant), some treatments including dietary control, drug therapy with a spherical carbonaceous absorbent, and anti-hypertensive drugs including ACEIs (angiotensin converting enzyme inhibitors) and ARBs (angiotensin receptor blockades) have shown some inhibition of the progression of CRF. These treatments are still not effective enough to curtail this increase. Therefore, the development of new effective drugs preventing the progression of CRF is still urgently required. In the present article, we show the first indication that Uremic Clearance Granule could be such a candidate.
Uremic Clearance Granule (Niaoduqing Keli in Chinese) (GUANGZHOU CONSUN PHARMACEUTICAL CO., LTD, CHINA) is one of traditional Chinese herbal medicine having been used for treatment of CRF in clinic for many years. To explore the mechanism relates to therapeutic effects of Uremic Clearance Granules on CRF and provide the academic evidences for clinical application, we had done some researches at DNA methylation modification, key gene mRNA and protein expression and disease-related metabolic products three levels using the Wister rats as the CRF model. The major results are shown as following:
Firstly, we examined the mRNA expression of the TGF-β1 and its downstream genes by SYBR Green Real-time fluorescent quantitative PCR, the protein expression of the TGF-β1 gene by Immunohistochemistry. A high level of TGF-(31 protein and mRNAs expression were identified in pathological control group while the level of TGF-β1 protein and mRNAs expression decreased comparatively in Uremic Clearance Granule-treatment group. The methylation status of TGF-β1 promoter in three groups was analyzed by methylation-specific PCR. There were three loci demethylated in TGF-β1 promoter of pathological rats, they were remathylated in Uremic Clearance Granule treatment group. The results showed that the treatment mechanism of Uremic Clearance Granule on CRF was to reduce expression of multiple genes which take the gene TGF-β1 as the center.
Secondly, Uremic Clearance Granule treatment could reduce the Homocysteine in rats blood, relieve Hyperhomocysteinemia (hHcys). The prevalence of hHcys in CRF patients is 82.5%, which is 2 to 3 times of normal level. Clinical and experimental studies suggested that hHomocysteine is also a risk factor for CRF. The Homocysteine (Hey) concentration in three different groups was determined by High Performance Liquid Chromatography. The data showed that the homocysteine concentration in Uremic Clearance Granule treatmeat rats reduced obviously compared to that in pathological control rats. The results indicate that Uremic Clearance Granule restore the renal function by homoeysteine clearing.
Thirdlv, the data showed that Uremic Clearance Granule restored genomic DNA methvlation to normal level. The accumulation of Homoevsteine in vivo leads to abnormal DNA methylation. Compared with normal control rats, we found the renal genomic DNA hypomethylation in pathological rats by MSAP analysis. Uremic Clearance Granule therapy restored it to normal level. The results reveal epigenetic mechanisms of Uremic Clearance Granule for treatment on Chronic Renal Failure.
As a summary, we educed that Uremic Clearance Granule treatment could clear the Homocysteine, restore DNA methylation to normal level and correct the patterns of gene expression. Clearance of Homocysteine has leaded to recovery of some genes methylation status may be one of molecular mechanisms of Uremic Clearance Granule as an effective treatment for CRF.
本论文以腺嘌呤饲喂法建立的慢性肾功能衰竭Wistar大鼠模型为实验材料,采用分子生物学的方法从DNA甲基化修饰、关键基因的mRNA及蛋白表达,以及疾病相关代谢产物三个层次系统地研究了尿毒清颗粒对慢性肾功能衰竭治疗的分子机制,研究结果为尿毒清颗粒在临床治疗上的应用提供了理论依据。主要结果如下：
1.通过本研究发现尿毒清颗粒可以在mRNA和蛋白质水平减少转化生长因子-β1 (TGF-β1)的表达。TGF-β1是引起肾小球硬化的主要介质,以其为靶向的治疗已成为近年来的研究热点。我们用SYBR Green实时荧光定量PCR技术检测了正常对照组大鼠、病理对照组大鼠和经尿毒清治疗后大鼠肾皮质TGF-β1及其下游基因mRNA的表达。为了确证TGF-β1 mRNA在本实验中表达升高是否引起了TGF-β1蛋白表达的增多,我们用免疫组织化学技术检测了大鼠肾皮质TGF-β1蛋白的表达。为了进一步研究各实验组TGF-β1表达变化出现的原因,我们用甲基化特异性PCR技术检测单基因TGF-β1启动子甲基化状态的变化,发现慢性肾功能衰竭大鼠TGF-β1启动子有些位点出现了去甲基化现象,而尿毒清颗粒治疗组该位点甲基化状态得到恢复。结果表明尿毒清颗粒对慢性肾功能衰竭的治疗是通过下调以TGF-β1为中心的多基因表达来进行的。
2.生化试验研究发现尿毒清颗粒可以降低慢性肾功能衰竭大鼠血清中同型半胱氨酸浓度,减轻高同型半胱氨酸血症。慢性肾功能衰竭患者血清同型半胱氨酸水平升高发生率高达82.5%,其水平为正常人的2-3倍。高同型半胱氨酸可能通过损害血管内皮,刺激血管平滑肌增殖等原因在慢性肾功能衰竭发病机制中起重要作用。我们用高效液相色谱检测了正常组对照大鼠、病理对照组大鼠和经尿毒清治疗后大鼠血清中同型半胱氨酸的含量,发现与病理对照组相比,经尿毒清治疗的大鼠血清同型半胱氨酸浓度显著下降。此结果揭示了尿毒清颗粒可以通过提高对同型半胱氨酸的清除达到恢复慢性肾功能衰竭大鼠肾功能的作用。
3.DNA甲基化研究发现尿毒清颗粒可以使慢性肾功能衰竭大鼠基因组DNA从低甲基化状态恢复到正常水平。同型半胱氨酸的积累会导致体内DNA甲基化异常,本实验对各组大鼠肾皮质基因组DNA甲基化状态进行甲基化敏感扩增多态性分析,结果发现慢性肾功能衰竭大鼠肾皮质基因组DNA出现了低甲基化现象,尿毒清颗粒治疗可以使其恢复为正常水平。结果揭示尿毒清颗粒可以通过表观遗传机制调节基因组DNA的甲基化状态来对慢性肾功能衰竭进行治疗。
上述研究结果表明：尿毒清颗粒能明显改善腺嘿吟诱导的慢性肾功能衰竭大鼠的肾功能,在mRNA和蛋白水平下调TGF-β1的表达,并通过对同型半胱氨酸的清除,缓解高同型半胱氦酸血症,改变慢性肾功能衰竭大鼠的去甲基化状态关闭TGF-β1基因的表达,通过多成分协作达到治疗作用。
Chronic Renal Failure (CRF) is a clinical syndrome associated with fluid, electrolyte, and hormone imbalances and metabolic abnormalities, which is a progressive loss of renal function over a period of months or years. There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. The number of patients with end-stage renal disease (ESRD) has increased rapidly over the last three decades, and prior to the advent of renal replacement therapy (dialysis and transplant), some treatments including dietary control, drug therapy with a spherical carbonaceous absorbent, and anti-hypertensive drugs including ACEIs (angiotensin converting enzyme inhibitors) and ARBs (angiotensin receptor blockades) have shown some inhibition of the progression of CRF. These treatments are still not effective enough to curtail this increase. Therefore, the development of new effective drugs preventing the progression of CRF is still urgently required. In the present article, we show the first indication that Uremic Clearance Granule could be such a candidate.
Uremic Clearance Granule (Niaoduqing Keli in Chinese) (GUANGZHOU CONSUN PHARMACEUTICAL CO., LTD, CHINA) is one of traditional Chinese herbal medicine having been used for treatment of CRF in clinic for many years. To explore the mechanism relates to therapeutic effects of Uremic Clearance Granules on CRF and provide the academic evidences for clinical application, we had done some researches at DNA methylation modification, key gene mRNA and protein expression and disease-related metabolic products three levels using the Wister rats as the CRF model. The major results are shown as following:
Firstly, we examined the mRNA expression of the TGF-β1 and its downstream genes by SYBR Green Real-time fluorescent quantitative PCR, the protein expression of the TGF-β1 gene by Immunohistochemistry. A high level of TGF-(31 protein and mRNAs expression were identified in pathological control group while the level of TGF-β1 protein and mRNAs expression decreased comparatively in Uremic Clearance Granule-treatment group. The methylation status of TGF-β1 promoter in three groups was analyzed by methylation-specific PCR. There were three loci demethylated in TGF-β1 promoter of pathological rats, they were remathylated in Uremic Clearance Granule treatment group. The results showed that the treatment mechanism of Uremic Clearance Granule on CRF was to reduce expression of multiple genes which take the gene TGF-β1 as the center.
Secondly, Uremic Clearance Granule treatment could reduce the Homocysteine in rats blood, relieve Hyperhomocysteinemia (hHcys). The prevalence of hHcys in CRF patients is 82.5%, which is 2 to 3 times of normal level. Clinical and experimental studies suggested that hHomocysteine is also a risk factor for CRF. The Homocysteine (Hey) concentration in three different groups was determined by High Performance Liquid Chromatography. The data showed that the homocysteine concentration in Uremic Clearance Granule treatmeat rats reduced obviously compared to that in pathological control rats. The results indicate that Uremic Clearance Granule restore the renal function by homoeysteine clearing.
Thirdlv, the data showed that Uremic Clearance Granule restored genomic DNA methvlation to normal level. The accumulation of Homoevsteine in vivo leads to abnormal DNA methylation. Compared with normal control rats, we found the renal genomic DNA hypomethylation in pathological rats by MSAP analysis. Uremic Clearance Granule therapy restored it to normal level. The results reveal epigenetic mechanisms of Uremic Clearance Granule for treatment on Chronic Renal Failure.
As a summary, we educed that Uremic Clearance Granule treatment could clear the Homocysteine, restore DNA methylation to normal level and correct the patterns of gene expression. Clearance of Homocysteine has leaded to recovery of some genes methylation status may be one of molecular mechanisms of Uremic Clearance Granule as an effective treatment for CRF.
引文
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