大黄酸对高糖环境下肾小管上皮细胞转分化的影响
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摘要
背景及目的
糖尿病肾病(Diabetic nephropathy,DN)是糖尿病主要的微血管并发症之一,肾小管间质纤维化是糖尿病肾病进展为终末期肾脏病(end stage renal disease,ESRD)的重要病理基础,细胞外基质(extracellular matrix,ECM)在肾间质过量堆积是其基本病理特征。目前认为肾间质ECM主要由肌成纤维细胞(myofibroblast,MyoF)产生。研究发现在病理条件下,肾小管上皮细胞可发生上皮细胞-肌成纤维细胞转分化(Tubular epithelial-myofibroblasttransdifferentiation,TEMT),即丧失原有的上皮细胞表型特征:E-钙粘蛋白(E-Cadherin),而获得MyoF的新特征:α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA),其是肾间质MyoF的重要来源。许多因素可诱导TEMT,而采用高糖模拟体内高血糖环境,肾小管上皮细胞是否发生TEMT?目前尚少见报道。
大黄是临床治疗慢性肾脏病处方中使用频率很高的一味中药。大黄酸(Rhein)是从大黄蒽醌衍生物中分离出的一种前体组分,为大黄的主要有效成分。糖尿病肾病动物模型中大黄酸具有减少蛋白尿,减轻肾组织病变的作用,其机制是否与TEMT有关目前尚未见报道,本实验采用大黄酸干预高糖环境下肾小管上皮细胞,观察大黄酸是否对TEMT有影响,试从TEMT这一途径阐述糖尿病肾病可能的发病机制及大黄酸对其的影响。
本研究模拟糖尿病高糖环境,体外培养人近端肾小管上皮细胞(human proximal tubular epithelial cells,HK-2),采用反映上皮细胞表型特征的E-Cadherin、反映MyoF表型特征的α-SMA和作为ECM成分之一的纤维连接蛋白(fibronectin,FN)等指标,观察高糖单因素作用下是否存在TEMT;并用大黄酸干预处理,观察其对TEMT的影响,初步探讨大黄酸防治糖尿病肾病的可能机制。
方法
按下列实验条件分六组培养HK-2细胞:空白对照(N组),低糖(5.5mmol/l)DMEM培养基;甘露醇(含24.5 mmol/l D-甘露醇+5.5mM D-葡萄糖)对照组(M组);高糖(H组)葡萄糖浓度30mmol/L;高糖+大黄酸25ug/ml(H+25R组);高糖+大黄酸50ug/ml(H+50R组);高糖+大黄酸100ug/ml(H+100R组),于48h观察细胞形态,收集各组细胞,western-blotting法检测E-Cadherin、α-SMA和FN蛋白水平。
结果
高糖组与低糖组比较,E-Cadherin蛋白表达减少(P＜0.05),α-SMA和FN蛋白表达增多(P＜0.05);甘露醇组与低糖组比较,E-Cadherin蛋白、α-SMA和FN蛋白表达无明显差异(P＞0.05)。经大黄酸处理后的各大黄酸组与高糖组比较E-Cadherin蛋白表达上调(P＜0.05),α-SMA和FN蛋白表达下调(P＜0.05),且与大黄酸呈剂量依赖性关系。
结论
1.高糖因素可导致HK-2细胞E-Cadherin蛋白表达减少,α-SMA和FN蛋白表达增加,提示高糖能促发TEMT。
2.大黄酸可抑制高糖环境下的HK-2细胞向MyoF转分化,阻抑TEMT,这可能是大黄酸防治DN的作用机制之一。
Background and objectives:
Diabetic nephropathy(DN)is one of blood capillary complications. Tubulointerstitial fibrosis is an essential pathological basis in the progression of diabetic nephropathy to end stage renal disease(ESRD), the basic pathological character of which is excessive extracellular matrix (ECM)accumulation in the renal interstitium.Currently,it is considered that the renal interstitial ECM is mainly secreted by the myofibroblast (MyoF).Researches have shown that tubular epithelial-myofibroblast transdifferentiation(TEMT)can occur to the renal tubular epithelial cells in pathological condition.During TEMT,renal tubular epithelial cells lose their original phenotypic characteristics:E-cadherin,then gain MyoF characteristics:α-smooth muscle actin(α-SMA),which is a principal source of renal interstitium MyoF.More and more concern is gradually focused on the role of TEMT in tubuinterstitial fibrosis.A considerable number of factors have been suggested as potential inductors of TEMT. However,it is still unknown whether the same TEMT process will take place with high glucose stimulation human proximal tubular epithelial cells(HK-2).
A traditional Chinese medicine frequently appears in clinical prescription,Rhein is a prosoma component extracted from the rhubarb anthraquinone ramifications and is the primary active ingredient of rhubarb.Rhein has the effect of decreasing proteinuria and attenuating nephridial tissue process in Diabetic Nephropathy,few is reported that the mechanism is related to TEMT process.Rhein intervenes in HK-2 in high glucose in our experience,then we observe whether TEMT process is influenced by Rhein and try to explain the possibility mechanism in diabetic nephropathy through TEMT.
From cell culture HK-2 in vitro,by imitation of high glucose and refering to indexes like fibronectin(FN),which is one of the ingredients of ECM,E-Cadherin andα-SMA,which respectively reflects the phenotypic characteristics of renal tubular epithelial cells and MyoF,the objective of this study is to illustrate the effect of high glucose on the phenotypic transformation of renal tubular epithelial cells,and to observe the influence of Rhein as an intervener in the above-mentioned processes,then initially probe the possibility of mechanism of rhein preventing and curing diabetic nephropathy.
Methods:
Human proximal tubular epithelial cells(HK-2)were divided into six groups:Group N,cultured with glucose(5.5mmol/l)DMEM;Group M,cultured with mammite(24.5mmol/l)and glucose(5.5mmol/L) DMEM;Group H,cultured with 30mmol/l glucose DMEM;Group H+25R,cultured with 30mmol/l glucose DMEM+Rhein 25ug/ml;Group H+50R,cultured with 30mmol/l glucose DMEM+Rhein 50ug/ml;Group H+100R,cultured with 30mmol/l glucose DMEM+Rhein 100ug/ml. Each group cells were collected at 48 hours when we observe cell morphology and the vary of protein expression of TEMT.The protein expression of E-Cadherin,α-SMA and FN were assessed by Western-blotting method.
Results.
Compared with group N,the protein expression of E-cadherin,α-SMA and FN in group M did not have distinct change(P＞0.05);the protein expression of E-cadherin in HK-2 cells decreased(P＜0.05);while the protein expression ofα-SMA and FN increased(P＜0.05)in high glucose environment(group H).The protein expression of E-cadherin increased(P＜0.05)while the protein expression ofα-SMA,FN decreased (P＜0.05)in Rhein treated group(group R)with dose-dependent manner, compared with group H(P＜0.05).
Conclusion:
1.With high glucose,the express of E-Cadherin protein decrease,while the express ofα-SMA and FN increase,indicating that high glucose can induce the phenotypic transformation of renal tubular epithelial cells into mesanchymal cells.
2.Rhein can repress the phenotypic transformation of renal tubular epithelial cells into mesanchymal cells and attenuate the process of TEMT, this may be a function mechanism of Rhein as a prevention to DN.
糖尿病肾病(Diabetic nephropathy,DN)是糖尿病主要的微血管并发症之一,肾小管间质纤维化是糖尿病肾病进展为终末期肾脏病(end stage renal disease,ESRD)的重要病理基础,细胞外基质(extracellular matrix,ECM)在肾间质过量堆积是其基本病理特征。目前认为肾间质ECM主要由肌成纤维细胞(myofibroblast,MyoF)产生。研究发现在病理条件下,肾小管上皮细胞可发生上皮细胞-肌成纤维细胞转分化(Tubular epithelial-myofibroblasttransdifferentiation,TEMT),即丧失原有的上皮细胞表型特征:E-钙粘蛋白(E-Cadherin),而获得MyoF的新特征:α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA),其是肾间质MyoF的重要来源。许多因素可诱导TEMT,而采用高糖模拟体内高血糖环境,肾小管上皮细胞是否发生TEMT?目前尚少见报道。
大黄是临床治疗慢性肾脏病处方中使用频率很高的一味中药。大黄酸(Rhein)是从大黄蒽醌衍生物中分离出的一种前体组分,为大黄的主要有效成分。糖尿病肾病动物模型中大黄酸具有减少蛋白尿,减轻肾组织病变的作用,其机制是否与TEMT有关目前尚未见报道,本实验采用大黄酸干预高糖环境下肾小管上皮细胞,观察大黄酸是否对TEMT有影响,试从TEMT这一途径阐述糖尿病肾病可能的发病机制及大黄酸对其的影响。
本研究模拟糖尿病高糖环境,体外培养人近端肾小管上皮细胞(human proximal tubular epithelial cells,HK-2),采用反映上皮细胞表型特征的E-Cadherin、反映MyoF表型特征的α-SMA和作为ECM成分之一的纤维连接蛋白(fibronectin,FN)等指标,观察高糖单因素作用下是否存在TEMT;并用大黄酸干预处理,观察其对TEMT的影响,初步探讨大黄酸防治糖尿病肾病的可能机制。
方法
按下列实验条件分六组培养HK-2细胞:空白对照(N组),低糖(5.5mmol/l)DMEM培养基;甘露醇(含24.5 mmol/l D-甘露醇+5.5mM D-葡萄糖)对照组(M组);高糖(H组)葡萄糖浓度30mmol/L;高糖+大黄酸25ug/ml(H+25R组);高糖+大黄酸50ug/ml(H+50R组);高糖+大黄酸100ug/ml(H+100R组),于48h观察细胞形态,收集各组细胞,western-blotting法检测E-Cadherin、α-SMA和FN蛋白水平。
结果
高糖组与低糖组比较,E-Cadherin蛋白表达减少(P＜0.05),α-SMA和FN蛋白表达增多(P＜0.05);甘露醇组与低糖组比较,E-Cadherin蛋白、α-SMA和FN蛋白表达无明显差异(P＞0.05)。经大黄酸处理后的各大黄酸组与高糖组比较E-Cadherin蛋白表达上调(P＜0.05),α-SMA和FN蛋白表达下调(P＜0.05),且与大黄酸呈剂量依赖性关系。
结论
1.高糖因素可导致HK-2细胞E-Cadherin蛋白表达减少,α-SMA和FN蛋白表达增加,提示高糖能促发TEMT。
2.大黄酸可抑制高糖环境下的HK-2细胞向MyoF转分化,阻抑TEMT,这可能是大黄酸防治DN的作用机制之一。
Background and objectives:
Diabetic nephropathy(DN)is one of blood capillary complications. Tubulointerstitial fibrosis is an essential pathological basis in the progression of diabetic nephropathy to end stage renal disease(ESRD), the basic pathological character of which is excessive extracellular matrix (ECM)accumulation in the renal interstitium.Currently,it is considered that the renal interstitial ECM is mainly secreted by the myofibroblast (MyoF).Researches have shown that tubular epithelial-myofibroblast transdifferentiation(TEMT)can occur to the renal tubular epithelial cells in pathological condition.During TEMT,renal tubular epithelial cells lose their original phenotypic characteristics:E-cadherin,then gain MyoF characteristics:α-smooth muscle actin(α-SMA),which is a principal source of renal interstitium MyoF.More and more concern is gradually focused on the role of TEMT in tubuinterstitial fibrosis.A considerable number of factors have been suggested as potential inductors of TEMT. However,it is still unknown whether the same TEMT process will take place with high glucose stimulation human proximal tubular epithelial cells(HK-2).
A traditional Chinese medicine frequently appears in clinical prescription,Rhein is a prosoma component extracted from the rhubarb anthraquinone ramifications and is the primary active ingredient of rhubarb.Rhein has the effect of decreasing proteinuria and attenuating nephridial tissue process in Diabetic Nephropathy,few is reported that the mechanism is related to TEMT process.Rhein intervenes in HK-2 in high glucose in our experience,then we observe whether TEMT process is influenced by Rhein and try to explain the possibility mechanism in diabetic nephropathy through TEMT.
From cell culture HK-2 in vitro,by imitation of high glucose and refering to indexes like fibronectin(FN),which is one of the ingredients of ECM,E-Cadherin andα-SMA,which respectively reflects the phenotypic characteristics of renal tubular epithelial cells and MyoF,the objective of this study is to illustrate the effect of high glucose on the phenotypic transformation of renal tubular epithelial cells,and to observe the influence of Rhein as an intervener in the above-mentioned processes,then initially probe the possibility of mechanism of rhein preventing and curing diabetic nephropathy.
Methods:
Human proximal tubular epithelial cells(HK-2)were divided into six groups:Group N,cultured with glucose(5.5mmol/l)DMEM;Group M,cultured with mammite(24.5mmol/l)and glucose(5.5mmol/L) DMEM;Group H,cultured with 30mmol/l glucose DMEM;Group H+25R,cultured with 30mmol/l glucose DMEM+Rhein 25ug/ml;Group H+50R,cultured with 30mmol/l glucose DMEM+Rhein 50ug/ml;Group H+100R,cultured with 30mmol/l glucose DMEM+Rhein 100ug/ml. Each group cells were collected at 48 hours when we observe cell morphology and the vary of protein expression of TEMT.The protein expression of E-Cadherin,α-SMA and FN were assessed by Western-blotting method.
Results.
Compared with group N,the protein expression of E-cadherin,α-SMA and FN in group M did not have distinct change(P＞0.05);the protein expression of E-cadherin in HK-2 cells decreased(P＜0.05);while the protein expression ofα-SMA and FN increased(P＜0.05)in high glucose environment(group H).The protein expression of E-cadherin increased(P＜0.05)while the protein expression ofα-SMA,FN decreased (P＜0.05)in Rhein treated group(group R)with dose-dependent manner, compared with group H(P＜0.05).
Conclusion:
1.With high glucose,the express of E-Cadherin protein decrease,while the express ofα-SMA and FN increase,indicating that high glucose can induce the phenotypic transformation of renal tubular epithelial cells into mesanchymal cells.
2.Rhein can repress the phenotypic transformation of renal tubular epithelial cells into mesanchymal cells and attenuate the process of TEMT, this may be a function mechanism of Rhein as a prevention to DN.
引文
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