肾脏组织醛固酮在环孢素A慢性肾毒性中作用的研究
摘要
研究背景
慢性肾毒性是限制环孢素A临床广泛应用的副作用之一。其发生机制与肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosteron system,RAAS)的激活有密切关系。RAAS激活不但可以引起肾脏血流动力学改变,还促使肾脏纤维化的发生。文献报道醛固酮拮抗剂安体舒通能减轻某些慢性肾脏病的肾间质纤维化,并延缓肾功能损害进展,提示醛固酮在这些肾脏病发病机制中可能具有重要作用。肾脏既是醛固酮作用的靶器官,又是产生醛固酮的器官。除肾上腺外,其他组织和器官产生的醛固酮均被称为组织醛固酮。目前,对肾组织醛固酮在环孢素A慢性肾毒性中的致病作用尚未见报道,本研究拟对其致病作用做一研究。
研究目的
1.建立肾上腺切除大鼠环孢素A慢性肾毒性模型,以便在排除循环醛固酮作用情况下,研究肾组织醛固酮致病作用。
2.利用上述模型,研究肾组织醛固酮在环孢素A慢性肾毒性中的致病作用及其作用机制,并观察选择性醛固酮受体抑制剂依普利酮干预后的影响。
3.研究肾上腺切除后,肾组织醛固酮能否释放入血,部分代偿循环醛固酮发挥维持电解质平衡的作用。
研究方法
32只雄性Sprague-Dawley大鼠分为4组:对照组(sham-ADX组),双侧肾上腺切除组(ADX组),双侧肾上腺切除+环孢素A组(CsA组),双侧肾上腺切除+环孢素A+依普利酮组(CsA+Epl组)。ADX组、CsA组和CsA+Epl组大鼠先行双侧肾上腺切除术,2周后分别给予安慰剂、环孢素A、环孢素A+依普利酮,sham-ADX组为假手术组。所有大鼠给予正常盐饮食,双侧肾上腺切除大鼠给予地塞米松12μg/kg/d替代治疗。6周后处死大鼠。在此6周观察期间留取血和尿,动态检测尿蛋白定量(Bradford法测定)、肌酐清除率(苦味酸法,自动生化分析仪测定)、血和尿醛固酮水平(酶免疫分析)、以及血和尿钠、钾水平(离子选择电极法,自动电解质仪测定)。处死大鼠后留取肾组织做肾组织半定量病理检查(石蜡切片Masson染色,数码图像分析),做肾组织转化生长因子-β1(TGF-β1)、结缔组织生长因子(CTGF)、纤溶酶原激活剂抑制物-1(PAI-1)及Ⅰ型胶原(Col-Ⅰ)的mRNA(实时荧光定量逆转录聚合酶链反应)和蛋白质表达检测(免疫组化染色),以及肾组织醛固酮合成酶CYP11B2 mRNA表达检测(实时荧光定量逆转录聚合酶链反应)和醛固酮水平测定(酶免疫分析)。
结果与讨论
1.各肾上腺切除组大鼠手术后检查肾上腺切除完整,第6周实验结束处死大鼠时也未发现肾上腺再生;术后第2天大鼠血和尿中检测不出醛固酮,尿钠排泄增加(p＜0.05)、血钠减低(p＜0.01),尿钾排泄减少(p＜0.05)、血钾上升(p＜0.05)。这些结果都提示上述大鼠双侧肾上腺全切成功。
2.肾上腺切除大鼠皮下注射环孢素A后,尿蛋白排泄增多(p＜0.01),肌酐清除率下降(p＜0.01),肾组织病理检查呈现明显肾间质纤维化(p＜0.01),提示环孢素A慢性肾毒性模型制作成功,此模型表现与低钠饮食所致环孢素A慢性肾毒性模型一致。实时荧光定量逆转录聚合酶链反应及免疫组化染色结果显示,肾组织Col-ⅠmRNA及蛋白质表达显著上调(p＜0.05),且TGF-β1、CTGF及PAI-1的mRNA及蛋白质表达也显著上调(p＜0.05)且Col-Ⅰ表达水平与后3者表达水平高度相关(p＜0.01),提示这些细胞因子可能参与了肾间质纤维化过程。
3.用依普利酮对上述环孢素A慢性肾毒性模型大鼠进行干预后,肾组织醛固酮合成酶CYP11B2 mRNA表达显著上调(p＜0.05),肾组织醛固酮水平显著增加(p＜0.01),提示依普利酮抑制醛固酮受体成功。干预后大鼠尿蛋白排泄显著减少(p＜0.01),肌酐清除率有所上升(差别尚无显著性,p＞0.05),肾间质纤维化显著减轻(p＜0.05);而且,肾组织中Col-Ⅰ、TGF-β1及PAI-1的mRNA及蛋白质表达显著下调(p＜0.05),CTGF的mRNA及蛋白质表达也有下调(差别尚无显著性,p＞0.05),说明依普利酮抑制醛固酮受体后,该模型大鼠肾脏病变明显减轻,这结果提示肾组织醛固酮参与了环孢素A慢性肾毒性模型发病。
4.第6周实验结束时,检测大鼠血及尿醛固酮已部分恢复,尿钠排泄和血钠水平已完全正常(与对照组比较p＞0.05),尿钾排泄和血钾水平也较术后2天时改善;并同时发现肾组织中醛固酮合成酶CYP11B2 mRNA表达显著上调(p＜0.05),肾组织醛固酮水平显著增高(p＜0.01)。这提示大鼠双侧肾上腺完整切除后,肾脏组织醛固酮合成会代偿性增加,并可能释放入血部分代偿循环醛固酮,以维持机体电解质平衡。
结论
1.大鼠双侧上腺切除造成低钠血症后皮下注射环孢素A,制作环孢素A慢性肾毒性模型获得成功。
2.应用依普利酮干预后,上述模型大鼠肾脏病变显著减轻,提示肾组织醛固酮参与了该模型致病。
3.双侧上腺切除消除循环醛固酮后,肾组织局部产生的醛固酮可能入血,部分代偿循环醛固酮,维持电解质平衡。
Background
Cyclosporine A(CsA) is an immunosuppressive drug used to prevent tissue allograft rejection.However,its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available.In the development of chronic CsA nephrotoxicity the renin-angiotensin-aldosterone system(RAAS) seems to play a crucial role.Not only does activation of RAAS impair renal hemodynamics,but enhance tubulointerstitial fibrosis.In recent years there has been a growing interest in the role of aldosterone in the pathophysiology of cardiovascular and renal diseases.It seems aldosterone plays an important role in chronic CsA nephrotoxicity because researchers reported spironolactone,which was aldosterone antagonist,not only reduced structural injury in chronic CsA nephrotoxicity,but also prevented renal dysfunction.These facts suggest that aldosterone acts as a key role in chronic CsA nephrotoxicity.The aldosterone synthesized outside adrenal gland has been called local or tissue aldosterone in order to make it different from circulatory aldosterone.Besides the target organ of aldostone,kidney is a producer of local aldosterone.However,it is not clear the role of local renal aldosterone in chronic CsA nephrotoxicity, which was this research's focus.
Objectives
First,we made a new chronic CsA nephrotoxity rat model by adrenalectomy without low sodium diet in order to observe the role of renal local aldosterone after circulatory aldosterone was eliminated.Then we evaluated the effect of local renal aldosterone on the progession of chronic CsA nephrotoxicity and the protective effect of eplerenone,a selective aldosterone antagonist,on renal function and structural alterations induced by CsA.Also we assessed whether the protective effect was associated with a reduction of transforming growth factor-β1(TGF-β1),connective tissue growth factor(CTGF) or plasminogen activator inhibitor-1(PAI-1).Finally the contribution of renal local aldosterone to cirulatory aldosterone and electrolyte balance.
Methods
32 male Sprague-Dawley rats weighing 300～320g were divided randomly into four groups:sham-ADX,ADX,CsA or CsA+Epl.Bilateral adrenalectomy was performed in all rats except rats in sham-ADX group. The second day after surgery,serum and urine aldosterone level were measured to confirm a completely bilateral adrenalectomy.After adrenalectomy,rats received dexamethasone 12μg/kg/d for replacement therapy to maintain normal glomerular filtration rate and fasting blood glucose.Normal sodium diet without 0.9%saline was provided.2 weeks after ADX,placebo,CsA(25mg/kg/d,subcutaneously) or CsA+Epl (100mg/kg/d,by gavage) were administrated to rats in different groups respectively.6 weeks later,all rats were sacrified and the following indicators were evaluated:
(1) urine protein excretion(Bradford method) and creatinine clearance (C_(cr),picric acid method,by autoanalyzer)
(2) aldosterone level in serum and urine(by enzyme immunoassay), serum natrium and potassium,urine natrium and potassium excretion(by autoanalyzer)
(3) tubulointerstitial fibrosis by masson trichrome stain
(4)TGF-β1,CTGF,PAI-land Col-ⅠmRNA level and protein expression in kidney by real-time quantitative PCR and immunohistochemistry.Also renal tissue aldosterone synthase CYP 11B2 mRNA expression and renal tissue aldosterone were measured.
Results and discussion
(1) The second day after ADX,serum and urine aldosterone were undetectable,with natriuresis(p＜0.05),hyponatremia(p＜0.01),decreased urine potassium excretion(p＜0.05) and hyperpotassaemia(p＜0.05). These data showed adrenals were removed intactly and no regeneration and the adrenalectomy was successful.
(2) Rats in CsA group showed increased urine protein,decreased C_(cr), tubulointerstitial fibrosis and there was statistic difference(p＜0.01).
These data demonstrated a successful model for chronic CsA nephrotoxity,which was similar with classic low sodium diet model.In renal tissues,these extracellular matrix and cytokines were seen upregulated,including Col-Ⅰ,TGF-β1,CTGF and PAI-1,which indicated that these cytokines maybe participate in tubulointerstitialfibrosis.
(3) After treatment by eplerenone,renal aldosterone synthase CYP11B2 mRNA and renal tissue aldosterone expression were upregulated(p＜0.05),which proved eplerenone inhibited aldosterone receptor.Urine protein excretion and tubulointerstitial fibrosis relieved by eplerenone(p＜0.01,p＜0.05 respectively) and clearance of creatinine was restored slightly although there was no significant difference(p＞0.05). Gene and protein expression of Col-Ⅰ,TGF-β1,CTGF and PAI-1 were downregulated although there was no no significant difference of CTGF expression(p＞0.05).
(4) At the endpoint,serum potassium,serum aldosterone,urine potassium and urine aldosterone excretion retrieved partially.Natrium in serum and urine was no significant difference compared with sham-ADX group(p＞0.05).Renal local aldosterone and its gene expression significantly upregulated(p＜0.01,p＜0.05 respectively).Based on these data,we hypothesized elevated renal local aldosterone in kidney after adrenalectomy maybe compensate for circulatory aldosterone to maintain electrolyte balance.
Conclusions
(1) We established a new model for chronic CsA nephtoxity by bilateral adrenalectomy without low sodium diet,which was used for renal local aldosterone research.
(2) Eplerenone reduced proteinuria,tubulointerstitial fibrosis by inhibition renal local aldosterone in this animal model.It indicated that renal local aldosterone played an important role in this chronic CsA nephrotoxity model.
(3) Renal local aldosterone maybe compensate for circulatory aldosterone to maintain electrolyte balance after adrenalectomy.
慢性肾毒性是限制环孢素A临床广泛应用的副作用之一。其发生机制与肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosteron system,RAAS)的激活有密切关系。RAAS激活不但可以引起肾脏血流动力学改变,还促使肾脏纤维化的发生。文献报道醛固酮拮抗剂安体舒通能减轻某些慢性肾脏病的肾间质纤维化,并延缓肾功能损害进展,提示醛固酮在这些肾脏病发病机制中可能具有重要作用。肾脏既是醛固酮作用的靶器官,又是产生醛固酮的器官。除肾上腺外,其他组织和器官产生的醛固酮均被称为组织醛固酮。目前,对肾组织醛固酮在环孢素A慢性肾毒性中的致病作用尚未见报道,本研究拟对其致病作用做一研究。
研究目的
1.建立肾上腺切除大鼠环孢素A慢性肾毒性模型,以便在排除循环醛固酮作用情况下,研究肾组织醛固酮致病作用。
2.利用上述模型,研究肾组织醛固酮在环孢素A慢性肾毒性中的致病作用及其作用机制,并观察选择性醛固酮受体抑制剂依普利酮干预后的影响。
3.研究肾上腺切除后,肾组织醛固酮能否释放入血,部分代偿循环醛固酮发挥维持电解质平衡的作用。
研究方法
32只雄性Sprague-Dawley大鼠分为4组:对照组(sham-ADX组),双侧肾上腺切除组(ADX组),双侧肾上腺切除+环孢素A组(CsA组),双侧肾上腺切除+环孢素A+依普利酮组(CsA+Epl组)。ADX组、CsA组和CsA+Epl组大鼠先行双侧肾上腺切除术,2周后分别给予安慰剂、环孢素A、环孢素A+依普利酮,sham-ADX组为假手术组。所有大鼠给予正常盐饮食,双侧肾上腺切除大鼠给予地塞米松12μg/kg/d替代治疗。6周后处死大鼠。在此6周观察期间留取血和尿,动态检测尿蛋白定量(Bradford法测定)、肌酐清除率(苦味酸法,自动生化分析仪测定)、血和尿醛固酮水平(酶免疫分析)、以及血和尿钠、钾水平(离子选择电极法,自动电解质仪测定)。处死大鼠后留取肾组织做肾组织半定量病理检查(石蜡切片Masson染色,数码图像分析),做肾组织转化生长因子-β1(TGF-β1)、结缔组织生长因子(CTGF)、纤溶酶原激活剂抑制物-1(PAI-1)及Ⅰ型胶原(Col-Ⅰ)的mRNA(实时荧光定量逆转录聚合酶链反应)和蛋白质表达检测(免疫组化染色),以及肾组织醛固酮合成酶CYP11B2 mRNA表达检测(实时荧光定量逆转录聚合酶链反应)和醛固酮水平测定(酶免疫分析)。
结果与讨论
1.各肾上腺切除组大鼠手术后检查肾上腺切除完整,第6周实验结束处死大鼠时也未发现肾上腺再生;术后第2天大鼠血和尿中检测不出醛固酮,尿钠排泄增加(p＜0.05)、血钠减低(p＜0.01),尿钾排泄减少(p＜0.05)、血钾上升(p＜0.05)。这些结果都提示上述大鼠双侧肾上腺全切成功。
2.肾上腺切除大鼠皮下注射环孢素A后,尿蛋白排泄增多(p＜0.01),肌酐清除率下降(p＜0.01),肾组织病理检查呈现明显肾间质纤维化(p＜0.01),提示环孢素A慢性肾毒性模型制作成功,此模型表现与低钠饮食所致环孢素A慢性肾毒性模型一致。实时荧光定量逆转录聚合酶链反应及免疫组化染色结果显示,肾组织Col-ⅠmRNA及蛋白质表达显著上调(p＜0.05),且TGF-β1、CTGF及PAI-1的mRNA及蛋白质表达也显著上调(p＜0.05)且Col-Ⅰ表达水平与后3者表达水平高度相关(p＜0.01),提示这些细胞因子可能参与了肾间质纤维化过程。
3.用依普利酮对上述环孢素A慢性肾毒性模型大鼠进行干预后,肾组织醛固酮合成酶CYP11B2 mRNA表达显著上调(p＜0.05),肾组织醛固酮水平显著增加(p＜0.01),提示依普利酮抑制醛固酮受体成功。干预后大鼠尿蛋白排泄显著减少(p＜0.01),肌酐清除率有所上升(差别尚无显著性,p＞0.05),肾间质纤维化显著减轻(p＜0.05);而且,肾组织中Col-Ⅰ、TGF-β1及PAI-1的mRNA及蛋白质表达显著下调(p＜0.05),CTGF的mRNA及蛋白质表达也有下调(差别尚无显著性,p＞0.05),说明依普利酮抑制醛固酮受体后,该模型大鼠肾脏病变明显减轻,这结果提示肾组织醛固酮参与了环孢素A慢性肾毒性模型发病。
4.第6周实验结束时,检测大鼠血及尿醛固酮已部分恢复,尿钠排泄和血钠水平已完全正常(与对照组比较p＞0.05),尿钾排泄和血钾水平也较术后2天时改善;并同时发现肾组织中醛固酮合成酶CYP11B2 mRNA表达显著上调(p＜0.05),肾组织醛固酮水平显著增高(p＜0.01)。这提示大鼠双侧肾上腺完整切除后,肾脏组织醛固酮合成会代偿性增加,并可能释放入血部分代偿循环醛固酮,以维持机体电解质平衡。
结论
1.大鼠双侧上腺切除造成低钠血症后皮下注射环孢素A,制作环孢素A慢性肾毒性模型获得成功。
2.应用依普利酮干预后,上述模型大鼠肾脏病变显著减轻,提示肾组织醛固酮参与了该模型致病。
3.双侧上腺切除消除循环醛固酮后,肾组织局部产生的醛固酮可能入血,部分代偿循环醛固酮,维持电解质平衡。
Background
Cyclosporine A(CsA) is an immunosuppressive drug used to prevent tissue allograft rejection.However,its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available.In the development of chronic CsA nephrotoxicity the renin-angiotensin-aldosterone system(RAAS) seems to play a crucial role.Not only does activation of RAAS impair renal hemodynamics,but enhance tubulointerstitial fibrosis.In recent years there has been a growing interest in the role of aldosterone in the pathophysiology of cardiovascular and renal diseases.It seems aldosterone plays an important role in chronic CsA nephrotoxicity because researchers reported spironolactone,which was aldosterone antagonist,not only reduced structural injury in chronic CsA nephrotoxicity,but also prevented renal dysfunction.These facts suggest that aldosterone acts as a key role in chronic CsA nephrotoxicity.The aldosterone synthesized outside adrenal gland has been called local or tissue aldosterone in order to make it different from circulatory aldosterone.Besides the target organ of aldostone,kidney is a producer of local aldosterone.However,it is not clear the role of local renal aldosterone in chronic CsA nephrotoxicity, which was this research's focus.
Objectives
First,we made a new chronic CsA nephrotoxity rat model by adrenalectomy without low sodium diet in order to observe the role of renal local aldosterone after circulatory aldosterone was eliminated.Then we evaluated the effect of local renal aldosterone on the progession of chronic CsA nephrotoxicity and the protective effect of eplerenone,a selective aldosterone antagonist,on renal function and structural alterations induced by CsA.Also we assessed whether the protective effect was associated with a reduction of transforming growth factor-β1(TGF-β1),connective tissue growth factor(CTGF) or plasminogen activator inhibitor-1(PAI-1).Finally the contribution of renal local aldosterone to cirulatory aldosterone and electrolyte balance.
Methods
32 male Sprague-Dawley rats weighing 300～320g were divided randomly into four groups:sham-ADX,ADX,CsA or CsA+Epl.Bilateral adrenalectomy was performed in all rats except rats in sham-ADX group. The second day after surgery,serum and urine aldosterone level were measured to confirm a completely bilateral adrenalectomy.After adrenalectomy,rats received dexamethasone 12μg/kg/d for replacement therapy to maintain normal glomerular filtration rate and fasting blood glucose.Normal sodium diet without 0.9%saline was provided.2 weeks after ADX,placebo,CsA(25mg/kg/d,subcutaneously) or CsA+Epl (100mg/kg/d,by gavage) were administrated to rats in different groups respectively.6 weeks later,all rats were sacrified and the following indicators were evaluated:
(1) urine protein excretion(Bradford method) and creatinine clearance (C_(cr),picric acid method,by autoanalyzer)
(2) aldosterone level in serum and urine(by enzyme immunoassay), serum natrium and potassium,urine natrium and potassium excretion(by autoanalyzer)
(3) tubulointerstitial fibrosis by masson trichrome stain
(4)TGF-β1,CTGF,PAI-land Col-ⅠmRNA level and protein expression in kidney by real-time quantitative PCR and immunohistochemistry.Also renal tissue aldosterone synthase CYP 11B2 mRNA expression and renal tissue aldosterone were measured.
Results and discussion
(1) The second day after ADX,serum and urine aldosterone were undetectable,with natriuresis(p＜0.05),hyponatremia(p＜0.01),decreased urine potassium excretion(p＜0.05) and hyperpotassaemia(p＜0.05). These data showed adrenals were removed intactly and no regeneration and the adrenalectomy was successful.
(2) Rats in CsA group showed increased urine protein,decreased C_(cr), tubulointerstitial fibrosis and there was statistic difference(p＜0.01).
These data demonstrated a successful model for chronic CsA nephrotoxity,which was similar with classic low sodium diet model.In renal tissues,these extracellular matrix and cytokines were seen upregulated,including Col-Ⅰ,TGF-β1,CTGF and PAI-1,which indicated that these cytokines maybe participate in tubulointerstitialfibrosis.
(3) After treatment by eplerenone,renal aldosterone synthase CYP11B2 mRNA and renal tissue aldosterone expression were upregulated(p＜0.05),which proved eplerenone inhibited aldosterone receptor.Urine protein excretion and tubulointerstitial fibrosis relieved by eplerenone(p＜0.01,p＜0.05 respectively) and clearance of creatinine was restored slightly although there was no significant difference(p＞0.05). Gene and protein expression of Col-Ⅰ,TGF-β1,CTGF and PAI-1 were downregulated although there was no no significant difference of CTGF expression(p＞0.05).
(4) At the endpoint,serum potassium,serum aldosterone,urine potassium and urine aldosterone excretion retrieved partially.Natrium in serum and urine was no significant difference compared with sham-ADX group(p＞0.05).Renal local aldosterone and its gene expression significantly upregulated(p＜0.01,p＜0.05 respectively).Based on these data,we hypothesized elevated renal local aldosterone in kidney after adrenalectomy maybe compensate for circulatory aldosterone to maintain electrolyte balance.
Conclusions
(1) We established a new model for chronic CsA nephtoxity by bilateral adrenalectomy without low sodium diet,which was used for renal local aldosterone research.
(2) Eplerenone reduced proteinuria,tubulointerstitial fibrosis by inhibition renal local aldosterone in this animal model.It indicated that renal local aldosterone played an important role in this chronic CsA nephrotoxity model.
(3) Renal local aldosterone maybe compensate for circulatory aldosterone to maintain electrolyte balance after adrenalectomy.
引文
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