基于β_3-AR探讨缩泉丸补肾缩尿的作用机制
摘要
祖国医学指出,肾为先天之本,肾虚是衰老的根本原因之一。肾气充足,能温煦膀胱,固摄有权,膀胱开阖有度,以维持水液的正常代谢。若因于先天禀赋不足,或病后失调,素体虚弱导致肾气不足,下元虚冷,失去固摄与司膀胱开阖作用,则膀胱气化制约功能失调而致多尿。缩泉丸出自《妇人良方》,由乌药、益智仁及山药组成,具有温肾祛寒,缩尿止遗的功效,主治膀胱虚寒证。现代被临床单独或者与其他药物联合使用,用来治疗尿频、遗尿、夜尿及尿失禁等泌尿系统疾病。
老年人的膀胱功能障碍发病率较高,除膀胱出口梗阻(bladder outlet obstruction, BOO)、盆底支持组织薄弱及神经疾患等明确病因外,尚可并发或单发临床无法解释的尿频、尿急及尿失禁等现象。对此,神经递质类药物疗效欠佳,说明还存在与老龄相关的逼尿肌自身特性的改变。膀胱的舒张机制中,胆碱能神经受体(M受体)的抑制和β肾上腺素能受体(β-AR)的兴奋最为主要。但M受体的数量和亲和力随着年龄的增加无明显改变,但是逼尿肌细胞的β-AR反应性降低,细胞中腺苷酸环化酶(adenylate cyclase, AC)活性及环磷酸腺苷(cyclic adenosine monophosphate, cAMP)水平相应下降。β-AR三种亚型都参与逼尿肌舒张功能的调节,但主要由β3-AR介导逼尿肌松弛。且β3-AR具有拮抗M受体的作用,可维持膀胱的顺应性和稳定性,其结构和功能的变化与老年人膀胱储尿功能障碍关系密切。
本课题前期研究表明缩泉丸对水负荷大鼠、小鼠和加用利尿药的大鼠均有显著的抗利尿作用,用药后Na+、Cl离子的排出显著减少,而K+排出增加,与醛固酮相似,因此从缩泉丸促进肾虚多尿大鼠醛固酮的合成与分泌方面的机理进行了探讨；同时立足于中医“肾”与神经内分泌系统的相关性,从改善下丘脑-垂体-肾上腺轴(hypothalamus-pituitary-adrenal, HPA)功能和调节作用于排尿中枢的神经递质及其受体的基因和蛋白表达方面也进行了研究；此外,还深入研究了缩泉丸对肾虚多尿模型水通道蛋白2 (aquaporin2,AQP2)的表达及其信号转导途径的影响。前期研究分别从神经内分泌、肾小管的重吸收和分泌等不同环节入手,在分子水平深入探讨了缩泉丸“温肾缩尿”的作用机制,为本课题的研究奠定了基础。鉴于此,本课题在前期影响神经内分泌系统及肾小管功能方面研究的基础上,将衰老-肾虚多尿-膀胱逼尿肌-神经受体结合研究,拟以调节膀胱逼尿肌舒张功能的神经受体β3-AR及其信号转导通路为切入点,结合内分泌免疫学指标,从分子药理学水平探讨缩泉丸“补肾缩尿”的作用机制。
本课题通过研究缩泉丸对自然衰老大鼠尿量及尿Na+、K+、Cl-离子浓度的影响,初步探讨了缩泉丸对肾虚多尿模型大鼠发挥“缩尿”作用的机制；通过对肾虚多尿模型大鼠血中醛固酮(aldosterone, ALD)及抗利尿激素(antidiuretic hormone, ADH)水平影响的实验研究,从内分泌角度观察了缩泉丸对肾虚多尿模型大鼠尿量的调节作用；通过ELISA法检测缩泉丸对肾虚多尿模型大鼠血中皮质醇(Cortisol, Cort)含量的影响及其对胸腺、脾脏及肾上腺等脏器系数的影响探讨缩泉丸对肾虚多尿模型大鼠发挥温肾作用的机制；采用荧光定量PCR和原位杂交的方法检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌中β3-ARmRNA表达的影响,采用ELISA法检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌中AC、cAMP及蛋白激酶A (protein kinase A, PKA)含量的影响,采用western blotting检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌PKA蛋白表达的影响,从分子药理学的角度探讨缩泉丸“补肾缩尿”的作用机制。
实验结果表明缩泉丸可明显减少肾虚多尿模型大鼠尿量；缩泉丸可使肾虚多尿模型大鼠尿Na+、Cl-排出减少,尿K+排出增加；缩泉丸可增加肾虚多尿模型大鼠血ALD及ADH的含量；缩泉丸能明显提高肾虚多尿模型大鼠脾脏、胸腺系数和肾上腺系数,从而改善肾虚多尿模型大鼠脾脏和胸腺、肾上腺的萎缩状态；缩泉丸可增加肾虚多尿模型大鼠血Cort含量；缩泉丸可使肾虚多尿模型大鼠膀胱逼尿肌中β3-ARmRNA的表达上调；缩泉丸可以增加肾虚多尿模型大鼠膀胱逼尿肌中AC、cAMP及PKA的含量；缩泉丸可以增加肾虚多尿模型大鼠膀胱逼尿肌中PKA蛋白的表达。
本课题选择以调节膀胱逼尿肌舒张功能的神经受体β3-AR及其信号转导通路为切入点,深入诠释和阐明缩泉丸在临床治疗“肾虚多尿”病证的分子药理学基础,充分说明中药复方多途经、多靶点、整体调节的治疗特色,为中医经典名方缩泉丸及“补肾缩尿”理论的现代研究提供新的思路与方法。
According to TCM's theory, Kidney is the origin of congenital constitution and kidney deficiency is one of the primarily causes of aging. If Kidney-Qi is adequate, the bladder can be much warmed, right astringent, opening and closing of a degree, in order to maintain normal metabolism of liquid water. If congenital deficiency or illness disorders, weak ferrite cause kidney deficiency, Xiayuan virtual cold, loss of bladder opening and closing effect, bladder dysfunction of gasification, which causes polyuria.The formula of Suoquanwan (SQW) is recorded in a Chinese medicine book named Furenliangfan, which collected hundreds of formulas of Chinese medicine combinations. SQW consists of three herb medicinesc Radix Linderase, Radix dioscorteae, 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 alone or be used in combination with other drugs, which is Polyuria and excessive urination due to Yang-deficiency of Kidney, such as enuresis, diabetes insipidus, noeturnalenuresis, neurogenic urinary frequen, chronic glomerulonephritis, nephrotic syndrome, urethral syndrome.
There is a higher incidence of bladder dysfunction in the elderly, in addition to such a clear cause as BOO, weak pelvic floor supporting tissues and nerve disorders, but can still be complicated by clinical or unexplained single urinary frequency, urgency, and incontinence and so on, for which neurotransmitters have poor drug efficacy, indicating that there are aging-related changes in detrusor own characteristics. Relaxation mechanism of the bladder, inhibition of cholinergic receptor (M receptor) and exciting ofβ-adrenergic receptor (β-AR) is the most major. However, the number of M receptor and affinity with increasing age did not change significantly, but reactivity ofβ-AR in the detrusor cell decreased, AC activity and cAMP levels decreased correspondingly.β-AR subtypes are involved in the regulation of detrusor relaxation, but detrusor relaxation mediated mainly by theβ3-AR.β3-AR and M receptor antagonistic effect can be maintained bladder compliance and stability. Changes of its structure and function are closely related to urine storage and bladder dysfunction in the elderly.
Previous studies of this subject have shown that SQW has a significant anti-diuretic effect on rats with water loading test and mice with a diuretic drug. After treatment, Na+, Cl- ion excretion was significantly reduced, while K+ excretion increased, which is similar to effects of aldosterone. Therefore, the mechanism of synthesis and secretion of aldosterone was investigated in kidney-deficiency rats with polyuria after administration SQW. While the study were processed from improving the HPA axis (hypothalamus-pituitary-adrenal axis) act and micturition central neurotransmitter and its receptor, gene and protein expression side, which also based on the "kidney" and the relevance of the neuroendocrine system. In addition, aquaporin 2 (AQP2) expressions and signal transduction pathway of kidney-deficiency rats with polyuria model after administration SQW also were studied. The theory of "warming kidney and stopping ployuria" were investgated respectively from neuroendocrine, renal tubular reabsorption and secretion of various aspects of starting depth at the molecular level, which laid the foundation of research about the subject.In view of this, the subject based on the neuroendocrine system the early renal tubular function studies, researched the old-Kidney deficiency and ployuria-Bladder detrusor-nerve receptors together, intended to regulate the diastolic function of the bladder detrusor neural receptorβ3-AR and its signal transduction research as a starting point, combined with endocrinology and immunological indicators, researched molecular pharmacology mechanism "nourishing kidney and stopping urination".
SQW can reduced the urination volume in the kidney-deficiency rats with polyuria model, which was investigated by studying preliminary urine and urinary Na+, K+, Cl- concentration of natural aging rats in this experiment. Regulation of SQW on kidney-deficiency rats with polyuria model was observed from the endocrine perspective through research the effects of plasma levels of ADH and ALD in rats. Effects of SQW on the content of Cort in serum was observed by ELISA and SWQ play a effect of warming kidney was observed by influence of SQW on thymus, spleen and adrenal weight. Effects of SQW on expression ofβ3-ARmRNA was detected by using fluorescence quantitative PCR and in situ hybridization method in the bladder detrusor of kidney-deficiency rats with polyuria model. Effects of SQW on the content of AC, cAMP and PKA was tested by using ELISA in the bladder detrusor of kidney-deficiency rats with polyuria model. Effects of SQW on the PKA protein expression was detected by western blotting in the bladder detrusor of kidney-deficiency rats with polyuria model. The mechanism of warming kidney and stopping ployuria" theory about SQW was evaluated from the perspective of molecular pharmacology.
It is a good and ideal kidney of Yang-deficiency and polyuria model. SQW can significantly reduce the urination volume in kidney-yang deficiency rats with polyuria. SQW can reduce Na+, Cl- emission and increased K+ excretion in kidney-yang deficiency rats with polyuria. SQW can increase the content of ALD and ADH in blood of kidney of Yang-deficiency and polyuria mode. SQW can increase significantly the spleen, thymus, adrenal coefficient and improved kidney spleen and thymus, adrenal atrophy state in kidney-yang deficiency rats with polyuria. SQW can increase the content of Cort in blood of kidney-yang deficiency rats with polyuria. SQW can elevate significantly the expression ofβ3-ARmRNA in bladder detrusor of kidney-yang deficiency rats with polyuria. SQW can also increase the content of AC, cAMP and PKA in bladder detrusor of kidney-yang deficiency rats with polyuria. SQW can elevate significantly the expression of PKA protein in bladder detrusor of kidney-yang deficiency rats with polyuria.
β3-AR of adjusting the bladder detrusor relaxation neural receptor and its signal transduction research were selected as a starting point, which deeply interpreted and clarified the basis of molecular pharmacology of SQW treatment diseases of Kidney-deficiency and polyuria, fully illustrated Chinese herbal compound multi-pass, multi-target, the overall adjustment of the treatment characteristics, provided new ideas and methods for the classical formula of SQW and modern research of "warming kidney and stopping ployuria" theory.
老年人的膀胱功能障碍发病率较高,除膀胱出口梗阻(bladder outlet obstruction, BOO)、盆底支持组织薄弱及神经疾患等明确病因外,尚可并发或单发临床无法解释的尿频、尿急及尿失禁等现象。对此,神经递质类药物疗效欠佳,说明还存在与老龄相关的逼尿肌自身特性的改变。膀胱的舒张机制中,胆碱能神经受体(M受体)的抑制和β肾上腺素能受体(β-AR)的兴奋最为主要。但M受体的数量和亲和力随着年龄的增加无明显改变,但是逼尿肌细胞的β-AR反应性降低,细胞中腺苷酸环化酶(adenylate cyclase, AC)活性及环磷酸腺苷(cyclic adenosine monophosphate, cAMP)水平相应下降。β-AR三种亚型都参与逼尿肌舒张功能的调节,但主要由β3-AR介导逼尿肌松弛。且β3-AR具有拮抗M受体的作用,可维持膀胱的顺应性和稳定性,其结构和功能的变化与老年人膀胱储尿功能障碍关系密切。
本课题前期研究表明缩泉丸对水负荷大鼠、小鼠和加用利尿药的大鼠均有显著的抗利尿作用,用药后Na+、Cl离子的排出显著减少,而K+排出增加,与醛固酮相似,因此从缩泉丸促进肾虚多尿大鼠醛固酮的合成与分泌方面的机理进行了探讨；同时立足于中医“肾”与神经内分泌系统的相关性,从改善下丘脑-垂体-肾上腺轴(hypothalamus-pituitary-adrenal, HPA)功能和调节作用于排尿中枢的神经递质及其受体的基因和蛋白表达方面也进行了研究；此外,还深入研究了缩泉丸对肾虚多尿模型水通道蛋白2 (aquaporin2,AQP2)的表达及其信号转导途径的影响。前期研究分别从神经内分泌、肾小管的重吸收和分泌等不同环节入手,在分子水平深入探讨了缩泉丸“温肾缩尿”的作用机制,为本课题的研究奠定了基础。鉴于此,本课题在前期影响神经内分泌系统及肾小管功能方面研究的基础上,将衰老-肾虚多尿-膀胱逼尿肌-神经受体结合研究,拟以调节膀胱逼尿肌舒张功能的神经受体β3-AR及其信号转导通路为切入点,结合内分泌免疫学指标,从分子药理学水平探讨缩泉丸“补肾缩尿”的作用机制。
本课题通过研究缩泉丸对自然衰老大鼠尿量及尿Na+、K+、Cl-离子浓度的影响,初步探讨了缩泉丸对肾虚多尿模型大鼠发挥“缩尿”作用的机制；通过对肾虚多尿模型大鼠血中醛固酮(aldosterone, ALD)及抗利尿激素(antidiuretic hormone, ADH)水平影响的实验研究,从内分泌角度观察了缩泉丸对肾虚多尿模型大鼠尿量的调节作用；通过ELISA法检测缩泉丸对肾虚多尿模型大鼠血中皮质醇(Cortisol, Cort)含量的影响及其对胸腺、脾脏及肾上腺等脏器系数的影响探讨缩泉丸对肾虚多尿模型大鼠发挥温肾作用的机制；采用荧光定量PCR和原位杂交的方法检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌中β3-ARmRNA表达的影响,采用ELISA法检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌中AC、cAMP及蛋白激酶A (protein kinase A, PKA)含量的影响,采用western blotting检测缩泉丸对肾虚多尿模型大鼠膀胱逼尿肌PKA蛋白表达的影响,从分子药理学的角度探讨缩泉丸“补肾缩尿”的作用机制。
实验结果表明缩泉丸可明显减少肾虚多尿模型大鼠尿量；缩泉丸可使肾虚多尿模型大鼠尿Na+、Cl-排出减少,尿K+排出增加；缩泉丸可增加肾虚多尿模型大鼠血ALD及ADH的含量；缩泉丸能明显提高肾虚多尿模型大鼠脾脏、胸腺系数和肾上腺系数,从而改善肾虚多尿模型大鼠脾脏和胸腺、肾上腺的萎缩状态；缩泉丸可增加肾虚多尿模型大鼠血Cort含量；缩泉丸可使肾虚多尿模型大鼠膀胱逼尿肌中β3-ARmRNA的表达上调；缩泉丸可以增加肾虚多尿模型大鼠膀胱逼尿肌中AC、cAMP及PKA的含量；缩泉丸可以增加肾虚多尿模型大鼠膀胱逼尿肌中PKA蛋白的表达。
本课题选择以调节膀胱逼尿肌舒张功能的神经受体β3-AR及其信号转导通路为切入点,深入诠释和阐明缩泉丸在临床治疗“肾虚多尿”病证的分子药理学基础,充分说明中药复方多途经、多靶点、整体调节的治疗特色,为中医经典名方缩泉丸及“补肾缩尿”理论的现代研究提供新的思路与方法。
According to TCM's theory, Kidney is the origin of congenital constitution and kidney deficiency is one of the primarily causes of aging. If Kidney-Qi is adequate, the bladder can be much warmed, right astringent, opening and closing of a degree, in order to maintain normal metabolism of liquid water. If congenital deficiency or illness disorders, weak ferrite cause kidney deficiency, Xiayuan virtual cold, loss of bladder opening and closing effect, bladder dysfunction of gasification, which causes polyuria.The formula of Suoquanwan (SQW) is recorded in a Chinese medicine book named Furenliangfan, which collected hundreds of formulas of Chinese medicine combinations. SQW consists of three herb medicinesc Radix Linderase, Radix dioscorteae, 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 alone or be used in combination with other drugs, which is Polyuria and excessive urination due to Yang-deficiency of Kidney, such as enuresis, diabetes insipidus, noeturnalenuresis, neurogenic urinary frequen, chronic glomerulonephritis, nephrotic syndrome, urethral syndrome.
There is a higher incidence of bladder dysfunction in the elderly, in addition to such a clear cause as BOO, weak pelvic floor supporting tissues and nerve disorders, but can still be complicated by clinical or unexplained single urinary frequency, urgency, and incontinence and so on, for which neurotransmitters have poor drug efficacy, indicating that there are aging-related changes in detrusor own characteristics. Relaxation mechanism of the bladder, inhibition of cholinergic receptor (M receptor) and exciting ofβ-adrenergic receptor (β-AR) is the most major. However, the number of M receptor and affinity with increasing age did not change significantly, but reactivity ofβ-AR in the detrusor cell decreased, AC activity and cAMP levels decreased correspondingly.β-AR subtypes are involved in the regulation of detrusor relaxation, but detrusor relaxation mediated mainly by theβ3-AR.β3-AR and M receptor antagonistic effect can be maintained bladder compliance and stability. Changes of its structure and function are closely related to urine storage and bladder dysfunction in the elderly.
Previous studies of this subject have shown that SQW has a significant anti-diuretic effect on rats with water loading test and mice with a diuretic drug. After treatment, Na+, Cl- ion excretion was significantly reduced, while K+ excretion increased, which is similar to effects of aldosterone. Therefore, the mechanism of synthesis and secretion of aldosterone was investigated in kidney-deficiency rats with polyuria after administration SQW. While the study were processed from improving the HPA axis (hypothalamus-pituitary-adrenal axis) act and micturition central neurotransmitter and its receptor, gene and protein expression side, which also based on the "kidney" and the relevance of the neuroendocrine system. In addition, aquaporin 2 (AQP2) expressions and signal transduction pathway of kidney-deficiency rats with polyuria model after administration SQW also were studied. The theory of "warming kidney and stopping ployuria" were investgated respectively from neuroendocrine, renal tubular reabsorption and secretion of various aspects of starting depth at the molecular level, which laid the foundation of research about the subject.In view of this, the subject based on the neuroendocrine system the early renal tubular function studies, researched the old-Kidney deficiency and ployuria-Bladder detrusor-nerve receptors together, intended to regulate the diastolic function of the bladder detrusor neural receptorβ3-AR and its signal transduction research as a starting point, combined with endocrinology and immunological indicators, researched molecular pharmacology mechanism "nourishing kidney and stopping urination".
SQW can reduced the urination volume in the kidney-deficiency rats with polyuria model, which was investigated by studying preliminary urine and urinary Na+, K+, Cl- concentration of natural aging rats in this experiment. Regulation of SQW on kidney-deficiency rats with polyuria model was observed from the endocrine perspective through research the effects of plasma levels of ADH and ALD in rats. Effects of SQW on the content of Cort in serum was observed by ELISA and SWQ play a effect of warming kidney was observed by influence of SQW on thymus, spleen and adrenal weight. Effects of SQW on expression ofβ3-ARmRNA was detected by using fluorescence quantitative PCR and in situ hybridization method in the bladder detrusor of kidney-deficiency rats with polyuria model. Effects of SQW on the content of AC, cAMP and PKA was tested by using ELISA in the bladder detrusor of kidney-deficiency rats with polyuria model. Effects of SQW on the PKA protein expression was detected by western blotting in the bladder detrusor of kidney-deficiency rats with polyuria model. The mechanism of warming kidney and stopping ployuria" theory about SQW was evaluated from the perspective of molecular pharmacology.
It is a good and ideal kidney of Yang-deficiency and polyuria model. SQW can significantly reduce the urination volume in kidney-yang deficiency rats with polyuria. SQW can reduce Na+, Cl- emission and increased K+ excretion in kidney-yang deficiency rats with polyuria. SQW can increase the content of ALD and ADH in blood of kidney of Yang-deficiency and polyuria mode. SQW can increase significantly the spleen, thymus, adrenal coefficient and improved kidney spleen and thymus, adrenal atrophy state in kidney-yang deficiency rats with polyuria. SQW can increase the content of Cort in blood of kidney-yang deficiency rats with polyuria. SQW can elevate significantly the expression ofβ3-ARmRNA in bladder detrusor of kidney-yang deficiency rats with polyuria. SQW can also increase the content of AC, cAMP and PKA in bladder detrusor of kidney-yang deficiency rats with polyuria. SQW can elevate significantly the expression of PKA protein in bladder detrusor of kidney-yang deficiency rats with polyuria.
β3-AR of adjusting the bladder detrusor relaxation neural receptor and its signal transduction research were selected as a starting point, which deeply interpreted and clarified the basis of molecular pharmacology of SQW treatment diseases of Kidney-deficiency and polyuria, fully illustrated Chinese herbal compound multi-pass, multi-target, the overall adjustment of the treatment characteristics, provided new ideas and methods for the classical formula of SQW and modern research of "warming kidney and stopping ployuria" theory.
引文
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