缩泉丸对醛固酮合成与分泌的调控机制研究
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摘要
缩泉丸出自《妇人良方》,由乌药、益智仁、山药组成,具有温肾祛寒、缩尿止遗的功效。主治肾阳虚所致的尿量增多、小便频数、遗尿。现代临床常用于治疗小儿遗尿、老年尿失禁、尿崩症、夜尿症、神经性尿频、尿道综合征等泌尿系统疾病,具有较好的疗效。
祖国医学认为,多尿病症的发生与肾气的温煦和膀胱的固摄功能密切相关。因此,温肾缩尿为治疗多尿行之有效的方法。本课题前期研究表明缩泉丸的抗利尿作用与该方保Na~+排K~+,促进醛固酮(ALD)的合成与分泌有关。醛固酮的合成和分泌受血管紧张素Ⅱ(AngⅡ)和促肾上腺皮质激素(ACTH)的调节,同时又有赖于其合成酶的催化,涉及肾素-血管紧张素-醛固酮系统(RAAS)、下丘脑-垂体-肾上腺皮质(HPA)轴和醛固酶合成酶催化途径的调节功能。在内分泌系统中,与肾阳虚关系最为密切的为HPA轴,同时,HPA轴与RAAS系统又可通过肾上腺皮质激素(ACTH)、AngⅡ影响ALD的合成与分泌,从而调节水液代谢。鉴于此,本课题选用缩泉丸通过调节HPA轴发挥“温肾”作用,影响HPA轴与RAAS系统发挥“缩尿”作用,温肾固本、缩尿治标,以醛固酮的合成与分泌调节为切入点,结合现代药理研究方法,通过对机体调节水液代谢的内分泌系统及醛固酮合成酶催化方面的实验研究,选取与醛固酮调节相关的指标,如与RAAS系统密切相关的肾素(PRA)、血管紧张素转化酶(ACE)、AngⅡ;与HPA轴密切相关的促肾上腺上质释放激素(CRH)、ACTH、环磷酸腺苷(cAMP);与合成酶催化相关的皮质酮(Cort)、醛固酮(ALD)等指标,通过实验对上述指标在肾虚多尿时及给药缩泉丸干预后动物体内含量及浓度的变化进行了研究,并结合血管紧张素Ⅰ型受体(AT1R)、醛固酮合成酶(CYP11B2)、醛固酮受体(MR)、ACTHmRNA及蛋白表达的变化研究,深入探讨缩泉丸影响醛固酮的合成与分泌的机制,确立了缩泉丸“温肾缩尿”作用机理的靶点,从而为缩泉丸多系统、多靶点治疗肾虚多尿提供了分子药理学基础,同时也为“温肾缩尿”理论的现代研究提供了一定的思路和方法。
本课题通过缩泉丸对腺嘌呤肾虚多尿大鼠脏器系数(胸腺、脾脏、肾上腺、垂体)及尿量、肾组织病理形态学、尿Na~+、K~+、Cl~-离子浓度等项指标的实验研究初步探讨了其对肾虚多尿模型大鼠发挥“温肾缩尿”作用的机制;通过对肾虚多尿模型大鼠垂体、肾上腺病理形态学影响的实验研究,从形态学角度观察了缩泉丸对肾虚多尿模型大鼠HPA轴的调节作用;通过ELISA法检测缩泉丸对肾虚多尿模型大鼠血中皮质酮(Cort)、醛固酮含量的影响,并采用RT-PCR法检测醛固酮合成酶CYP11BEmRNA表达的变化观察缩泉丸在酮固酮合成酶催化方面的调节作用;通过ELISA法测定缩泉丸对肾虚多尿模型大鼠血中肾素、AngⅡ含量的变化,生化法检测血清ACE活性变化,观察缩泉丸对RAAS系统的调节作用;采用放免法测定缩泉丸对肾虚多尿模型大鼠血中cAMP含量的影响,ELISA法测定血中ACTH、CRH含量的变化,观察其对HPA轴的调节作用;采用RT-PCR的方法检测缩泉丸对肾虚多尿模型大鼠肾脏AT1R、MRmRNA及垂体ACTHmRNA表达的影响;采用免疫组化方法检测缩泉丸对肾虚多尿模型大鼠肾脏AT1R、MR及垂体ACTH蛋白表达的影响,从分子药理学的角度观察其作用机理。
实验结果表明,缩泉丸可明显减少肾虚多尿模型大鼠的尿量;可使肾虚多尿模型大鼠尿Na~+、Cl~-排出减少,尿K~+排出增加;能明显提高肾虚多尿模型大鼠脾脏、胸腺系数和垂体、肾上腺系数,从而改善肾虚多尿模型大鼠脾脏和胸腺、肾上腺和垂体的萎缩状态;可增加肾虚多尿模型大鼠血中PRA、ACE、AngⅡ、ALD、Cort及CRH、ACTH、cAMP含量;可以改善肾虚多尿模型大鼠肾脏的病理变化,使肾小管腔的棕黄色结晶沉积、减轻肾小管的扩张;可改善肾虚多尿模型大鼠肾上腺、垂体的形态学变化,使垂体与肾上腺形态结构基本恢复正常,改善肾上腺皮质部球状带与网状带的萎缩状态;可使肾虚多尿模型大鼠肾脏AT1R、MR、CYP1182mRNA、垂体ACTHmRNA的表达上调;使肾虚多尿模型大鼠肾脏AT1R、MR、垂体ACTH蛋白的表达增加。
上述实验研究结果初步阐明了缩泉丸通过调节ALD的合成与分泌发挥“温肾缩尿”作用的机制,主要与以下两个方面有关:首先从ALD合成的角度表明其可能通过增加血中Cort含量及上调CYP1182mRNA的表达,催化醛固酮的合成,提高其在血中的含量,从而促进水液代谢的调节发挥“缩尿”作用,其促进ALD合成的作用靶点可能与CYP11B2有关;再者从调节内分泌的角度说明了其作用机制与两条内分泌途径的相关性:一可通过增加血中CRH、ACTH、cAMP的含量,改善垂体、肾上腺形态学的变化,增加ACTHmRNA及蛋白的表达,上调HPA轴的功能,促进ALD的合成与分泌发挥“缩尿”作用,HPA轴功能的上调又可使肾阳虚状态得到改善。此外,还可能通过增加胸腺、脾脏、垂体、肾上腺的重量,改善机体的免疫功能,从而发挥一定的“温补肾阳”作用,并表明其调节HPA轴的分子药理学机制与影响ACTHmRNA及蛋白的表达有关;二可通过增加血中PRA、ACE、AngⅡ的含量,上调AT1R、MRmRNA及蛋白的表达,促进RAAS系统功能,从而促进ALD的合成与分泌,调节水液代谢发挥“缩尿”作用。并通过基因及蛋白表达变化的研究表明其调节RAAS系统的作用靶点与AT1R、MR有关。
本课题通过对醛固酮合成与分泌的调节作用及作用靶点MR、AT1R、CYP1182、ACTH的理论与实验研究,从多系统、多靶点、整体调节的角度阐明了缩泉丸调节ALD合成与分泌发挥“温肾缩尿”作用的深层次机理。
The formula of Suoquanwan(SQW) is recorded in a Chinese medicine book named Furenliangfang,which collected hundreds of formulas of Chinese medicine combinations.SQW consists of three herb medicines,Radix Linderae,Radix dioscoreae,and alpinia oxyphylla Miq.The function of SQW is to warm kidney,stop polyuria and hold excessive urination.In clinical practice,SQW is used for the treatment of urinary system diseases,which is polyuria and excessive urination due to Yang-deficiency of Kidney,such as enuresis,diabetes insipidus, nocturnal enuresis,neurogenic urinary frequency,Chronic glomerulonephritis,Nephrotic syndrome,Urethral syndrome.
According to TCM's theory,polyuria is closely related to the function of Kidndy and bladder,that is,warm kidney and hold excessive urination can effectively cure the disease.Investigation in the earlier stage showed that its function of anti-diuresis was connected with retaining sodium and arranging potassium,and also promoting the combining and secretion of aldosterone,adjusted by AngⅡ,ACTH,which was involved in endocriniums,such as RAAS,HPA.In endocriniums,HPA can affect the function of kidney,and HPA and RAAS can also adjust liquid metabolism by AngⅡ,ACTH's affection to the combinign and excretion of ALD.According to the above analyse,focus on the combining and secretion of aldosterone,the thesis chose SQW to act to warm kidney and hold excessive urination and compared the concentration and contents of PRA,ACE, AngⅡ,ALD,ACTH,cAMP in blood when Yang-deficiency of Kidey with after oral administration of SQW,and also explored its mechanism of affecting the combining and secretion of aldosterone,established the target spots by observing the mRNA and protein expressions of AT1R,MR,ACTH, GYP11B2.Through the above experiments,the thesis provided molecular pharmacology mechanism for SQW and expounded its therapy characteristics of multisystem and multi- target spots.
The thesis explored SQW's therapy effect and adjusting function to endocriniums in kidney-yang deficiency rats with polyuria by detecting the weight of thymus gland,spleen,adrenal gland,hypophysis,urine and the concentration of ions in urine.By observing pathology morphology change of the adrenal gland,hypophysis and the contents change of CRH、Cort、cAMP,ACTH,PRA,ALD,AngⅡ,ACE in blood,the study expounded its adjusting function to HPA、RAAS and the compound of ALD.The investigation also revealed SQW's molecular pharmacology mechanism after detecting mRNA and protein expressions of AT1R,MR,ACTH,CP11B2 by the mothed of RT-PCR and immunohistochemistry.
The results show that SQW reduces significantly the urine and the concentration of sodium,chlorine in urine,and elevate urine potassium excretion in kidney-yang deficiency rats with polyuria.SQW can improve the atrophy state of thymus gland,spleen,adrenal gland,hypophysis by increasing its weight.The contents of CRH,Cort,ACE,AngⅡ,ALD,ACTH, cAMP increase after SQW administration in model rats.The pathological characteristics of kidney and adrenal gland,hypophysis of model rats are switched.By RT-PCT and immunohistochemistry,both mRNA and protein expressions of AT1R,MR,ACTH,CYP11B2 are increased.
The thesis expounds the pharmacology mechanism of SQW in nourishing kidney and reducing urine.At first,SQW can promote the combining of ALD by increasing the content of Cort,and also adjusting the mRNA expression of CYP11B2.The target is related to CYP11B2.And then,SQW can treat kidney-yang deficiency with polyuria by affecting endocriniums,which includes two approachs.One is that SQW can hold excessive urination by adjusting the combining and excretion of ALD.Its mechanism is to adjust HPA by changing the content of CRH,ACTH,cAMP in blood,improving the pathological characteristics of adrenal gland,hypophysis and by so doing,its function of nourishing kidney is correspondingly enhanced.Besides that,SQW can improv immune function by increasing the weight of imune organs,which also lead to the enhancement of HPA'effect.In short words,SQW's nourishing kidney is mainly connected with the above two factors.Its target spot in HPA is related to ACTH.Another is that SQW adjusts RAAS by affecting the contents of PRA,ACE,AngⅡin blood.And its target spots in RAAS are connected with AT1R、MR.
The thesis confirms the therapy's characteristics of SQW,which are multi-target,multi-system,integral regulation,and also expounds its connotation of nourishing kidney and reducing urine,which involved in RAAS,HPA and MR,AT1R,CYP11B2,ACTH.
祖国医学认为,多尿病症的发生与肾气的温煦和膀胱的固摄功能密切相关。因此,温肾缩尿为治疗多尿行之有效的方法。本课题前期研究表明缩泉丸的抗利尿作用与该方保Na~+排K~+,促进醛固酮(ALD)的合成与分泌有关。醛固酮的合成和分泌受血管紧张素Ⅱ(AngⅡ)和促肾上腺皮质激素(ACTH)的调节,同时又有赖于其合成酶的催化,涉及肾素-血管紧张素-醛固酮系统(RAAS)、下丘脑-垂体-肾上腺皮质(HPA)轴和醛固酶合成酶催化途径的调节功能。在内分泌系统中,与肾阳虚关系最为密切的为HPA轴,同时,HPA轴与RAAS系统又可通过肾上腺皮质激素(ACTH)、AngⅡ影响ALD的合成与分泌,从而调节水液代谢。鉴于此,本课题选用缩泉丸通过调节HPA轴发挥“温肾”作用,影响HPA轴与RAAS系统发挥“缩尿”作用,温肾固本、缩尿治标,以醛固酮的合成与分泌调节为切入点,结合现代药理研究方法,通过对机体调节水液代谢的内分泌系统及醛固酮合成酶催化方面的实验研究,选取与醛固酮调节相关的指标,如与RAAS系统密切相关的肾素(PRA)、血管紧张素转化酶(ACE)、AngⅡ;与HPA轴密切相关的促肾上腺上质释放激素(CRH)、ACTH、环磷酸腺苷(cAMP);与合成酶催化相关的皮质酮(Cort)、醛固酮(ALD)等指标,通过实验对上述指标在肾虚多尿时及给药缩泉丸干预后动物体内含量及浓度的变化进行了研究,并结合血管紧张素Ⅰ型受体(AT1R)、醛固酮合成酶(CYP11B2)、醛固酮受体(MR)、ACTHmRNA及蛋白表达的变化研究,深入探讨缩泉丸影响醛固酮的合成与分泌的机制,确立了缩泉丸“温肾缩尿”作用机理的靶点,从而为缩泉丸多系统、多靶点治疗肾虚多尿提供了分子药理学基础,同时也为“温肾缩尿”理论的现代研究提供了一定的思路和方法。
本课题通过缩泉丸对腺嘌呤肾虚多尿大鼠脏器系数(胸腺、脾脏、肾上腺、垂体)及尿量、肾组织病理形态学、尿Na~+、K~+、Cl~-离子浓度等项指标的实验研究初步探讨了其对肾虚多尿模型大鼠发挥“温肾缩尿”作用的机制;通过对肾虚多尿模型大鼠垂体、肾上腺病理形态学影响的实验研究,从形态学角度观察了缩泉丸对肾虚多尿模型大鼠HPA轴的调节作用;通过ELISA法检测缩泉丸对肾虚多尿模型大鼠血中皮质酮(Cort)、醛固酮含量的影响,并采用RT-PCR法检测醛固酮合成酶CYP11BEmRNA表达的变化观察缩泉丸在酮固酮合成酶催化方面的调节作用;通过ELISA法测定缩泉丸对肾虚多尿模型大鼠血中肾素、AngⅡ含量的变化,生化法检测血清ACE活性变化,观察缩泉丸对RAAS系统的调节作用;采用放免法测定缩泉丸对肾虚多尿模型大鼠血中cAMP含量的影响,ELISA法测定血中ACTH、CRH含量的变化,观察其对HPA轴的调节作用;采用RT-PCR的方法检测缩泉丸对肾虚多尿模型大鼠肾脏AT1R、MRmRNA及垂体ACTHmRNA表达的影响;采用免疫组化方法检测缩泉丸对肾虚多尿模型大鼠肾脏AT1R、MR及垂体ACTH蛋白表达的影响,从分子药理学的角度观察其作用机理。
实验结果表明,缩泉丸可明显减少肾虚多尿模型大鼠的尿量;可使肾虚多尿模型大鼠尿Na~+、Cl~-排出减少,尿K~+排出增加;能明显提高肾虚多尿模型大鼠脾脏、胸腺系数和垂体、肾上腺系数,从而改善肾虚多尿模型大鼠脾脏和胸腺、肾上腺和垂体的萎缩状态;可增加肾虚多尿模型大鼠血中PRA、ACE、AngⅡ、ALD、Cort及CRH、ACTH、cAMP含量;可以改善肾虚多尿模型大鼠肾脏的病理变化,使肾小管腔的棕黄色结晶沉积、减轻肾小管的扩张;可改善肾虚多尿模型大鼠肾上腺、垂体的形态学变化,使垂体与肾上腺形态结构基本恢复正常,改善肾上腺皮质部球状带与网状带的萎缩状态;可使肾虚多尿模型大鼠肾脏AT1R、MR、CYP1182mRNA、垂体ACTHmRNA的表达上调;使肾虚多尿模型大鼠肾脏AT1R、MR、垂体ACTH蛋白的表达增加。
上述实验研究结果初步阐明了缩泉丸通过调节ALD的合成与分泌发挥“温肾缩尿”作用的机制,主要与以下两个方面有关:首先从ALD合成的角度表明其可能通过增加血中Cort含量及上调CYP1182mRNA的表达,催化醛固酮的合成,提高其在血中的含量,从而促进水液代谢的调节发挥“缩尿”作用,其促进ALD合成的作用靶点可能与CYP11B2有关;再者从调节内分泌的角度说明了其作用机制与两条内分泌途径的相关性:一可通过增加血中CRH、ACTH、cAMP的含量,改善垂体、肾上腺形态学的变化,增加ACTHmRNA及蛋白的表达,上调HPA轴的功能,促进ALD的合成与分泌发挥“缩尿”作用,HPA轴功能的上调又可使肾阳虚状态得到改善。此外,还可能通过增加胸腺、脾脏、垂体、肾上腺的重量,改善机体的免疫功能,从而发挥一定的“温补肾阳”作用,并表明其调节HPA轴的分子药理学机制与影响ACTHmRNA及蛋白的表达有关;二可通过增加血中PRA、ACE、AngⅡ的含量,上调AT1R、MRmRNA及蛋白的表达,促进RAAS系统功能,从而促进ALD的合成与分泌,调节水液代谢发挥“缩尿”作用。并通过基因及蛋白表达变化的研究表明其调节RAAS系统的作用靶点与AT1R、MR有关。
本课题通过对醛固酮合成与分泌的调节作用及作用靶点MR、AT1R、CYP1182、ACTH的理论与实验研究,从多系统、多靶点、整体调节的角度阐明了缩泉丸调节ALD合成与分泌发挥“温肾缩尿”作用的深层次机理。
The formula of Suoquanwan(SQW) is recorded in a Chinese medicine book named Furenliangfang,which collected hundreds of formulas of Chinese medicine combinations.SQW consists of three herb medicines,Radix Linderae,Radix dioscoreae,and alpinia oxyphylla Miq.The function of SQW is to warm kidney,stop polyuria and hold excessive urination.In clinical practice,SQW is used for the treatment of urinary system diseases,which is polyuria and excessive urination due to Yang-deficiency of Kidney,such as enuresis,diabetes insipidus, nocturnal enuresis,neurogenic urinary frequency,Chronic glomerulonephritis,Nephrotic syndrome,Urethral syndrome.
According to TCM's theory,polyuria is closely related to the function of Kidndy and bladder,that is,warm kidney and hold excessive urination can effectively cure the disease.Investigation in the earlier stage showed that its function of anti-diuresis was connected with retaining sodium and arranging potassium,and also promoting the combining and secretion of aldosterone,adjusted by AngⅡ,ACTH,which was involved in endocriniums,such as RAAS,HPA.In endocriniums,HPA can affect the function of kidney,and HPA and RAAS can also adjust liquid metabolism by AngⅡ,ACTH's affection to the combinign and excretion of ALD.According to the above analyse,focus on the combining and secretion of aldosterone,the thesis chose SQW to act to warm kidney and hold excessive urination and compared the concentration and contents of PRA,ACE, AngⅡ,ALD,ACTH,cAMP in blood when Yang-deficiency of Kidey with after oral administration of SQW,and also explored its mechanism of affecting the combining and secretion of aldosterone,established the target spots by observing the mRNA and protein expressions of AT1R,MR,ACTH, GYP11B2.Through the above experiments,the thesis provided molecular pharmacology mechanism for SQW and expounded its therapy characteristics of multisystem and multi- target spots.
The thesis explored SQW's therapy effect and adjusting function to endocriniums in kidney-yang deficiency rats with polyuria by detecting the weight of thymus gland,spleen,adrenal gland,hypophysis,urine and the concentration of ions in urine.By observing pathology morphology change of the adrenal gland,hypophysis and the contents change of CRH、Cort、cAMP,ACTH,PRA,ALD,AngⅡ,ACE in blood,the study expounded its adjusting function to HPA、RAAS and the compound of ALD.The investigation also revealed SQW's molecular pharmacology mechanism after detecting mRNA and protein expressions of AT1R,MR,ACTH,CP11B2 by the mothed of RT-PCR and immunohistochemistry.
The results show that SQW reduces significantly the urine and the concentration of sodium,chlorine in urine,and elevate urine potassium excretion in kidney-yang deficiency rats with polyuria.SQW can improve the atrophy state of thymus gland,spleen,adrenal gland,hypophysis by increasing its weight.The contents of CRH,Cort,ACE,AngⅡ,ALD,ACTH, cAMP increase after SQW administration in model rats.The pathological characteristics of kidney and adrenal gland,hypophysis of model rats are switched.By RT-PCT and immunohistochemistry,both mRNA and protein expressions of AT1R,MR,ACTH,CYP11B2 are increased.
The thesis expounds the pharmacology mechanism of SQW in nourishing kidney and reducing urine.At first,SQW can promote the combining of ALD by increasing the content of Cort,and also adjusting the mRNA expression of CYP11B2.The target is related to CYP11B2.And then,SQW can treat kidney-yang deficiency with polyuria by affecting endocriniums,which includes two approachs.One is that SQW can hold excessive urination by adjusting the combining and excretion of ALD.Its mechanism is to adjust HPA by changing the content of CRH,ACTH,cAMP in blood,improving the pathological characteristics of adrenal gland,hypophysis and by so doing,its function of nourishing kidney is correspondingly enhanced.Besides that,SQW can improv immune function by increasing the weight of imune organs,which also lead to the enhancement of HPA'effect.In short words,SQW's nourishing kidney is mainly connected with the above two factors.Its target spot in HPA is related to ACTH.Another is that SQW adjusts RAAS by affecting the contents of PRA,ACE,AngⅡin blood.And its target spots in RAAS are connected with AT1R、MR.
The thesis confirms the therapy's characteristics of SQW,which are multi-target,multi-system,integral regulation,and also expounds its connotation of nourishing kidney and reducing urine,which involved in RAAS,HPA and MR,AT1R,CYP11B2,ACTH.
引文
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