丹参酮ⅡA和Notch信号通路与肾纤维化的研究进展
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摘要
肾纤维化是慢性肾脏病的特征性病理学变化,主要表现为大量细胞外基质沉淀、肾脏组织结构破坏、肾脏功能受损等。丹参酮ⅡA作为丹参的脂溶性有效成分,对抑制肾纤维化具有一定效果。丹参酮ⅡA可通过抗炎、抗氧化等方式治疗肾脏损害,并可通过参与肾纤维化信号通路转导,影响信号通路中调节因子和目的蛋白的生成,从而延缓肾纤维化的进程。Notch信号通路可以通过调节自身信号途径产物的表达,直接调控肾纤维化过程,并与其他信号途径相互串联,共同影响肾纤维化的进展。
Renal fibrosis is a characteristic pathological change of chronic kidney disease,which is characterized by a large amount of extracellular matrix deposition,destruction of renal tissue structure,and impaired renal function etc. As a fat-soluble active ingredient of Salvia miltiorrhiza,Tanshinone ⅡA contributes to inhibiting renal fibrosis. Tanshinone ⅡA can treat kidney injury through anti-inflammatory and anti-oxidation approaches,and it affects both the regulatory factors and the production of target proteins of the signaling pathways through participating in renal fibrosis signaling pathway,which eventually delays the progression of renal fibrosis. The Notch signaling pathway can directly regulate the renal fibrosis process by controlling the expression of its own signaling pathway products,and it can be cascaded with other signaling pathways to affect the progression of renal fibrosis collectively.
Renal fibrosis is a characteristic pathological change of chronic kidney disease,which is characterized by a large amount of extracellular matrix deposition,destruction of renal tissue structure,and impaired renal function etc. As a fat-soluble active ingredient of Salvia miltiorrhiza,Tanshinone ⅡA contributes to inhibiting renal fibrosis. Tanshinone ⅡA can treat kidney injury through anti-inflammatory and anti-oxidation approaches,and it affects both the regulatory factors and the production of target proteins of the signaling pathways through participating in renal fibrosis signaling pathway,which eventually delays the progression of renal fibrosis. The Notch signaling pathway can directly regulate the renal fibrosis process by controlling the expression of its own signaling pathway products,and it can be cascaded with other signaling pathways to affect the progression of renal fibrosis collectively.
引文
[1]Djudjaj S,Boor P,Peter B.Cellular and molecular mechanisms of kidney fibrosis[J].Mol Aspects Med,2019,65:16-36.
[2]Leask A.Targeting the jagged/notch pathway:A new treatment for fibrosis?[J].J Cell Commun Signal,2010,4(4):197-198.
[3]Xiao Z,Zhang J,Peng X,et al.The Notchγ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation[J].Int J Biochem Cell Biol,2014,55:65-71.
[4]Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:Cell fate control and signal integration in development[J].Science,1999,284(5415):770-776.
[5]Grieselhuber NR,Klco JM,Verdoni AM,et al.Notch signaling in acute promyelocytic leukemia[J].Leukemia,2013,27(7):1548-1557.
[6]Schwanbeck R,Martini S,Bernoth K,et al.The Notch signaling pathway:Molecular basis of cell context dependency[J].Eur JCell Biol,2011,90(6/7):572-581.
[7]Hori K,Sen A,Artavanis-Tsakonas S.Notch signaling at a glance[J].J Cell Sci,2013,126(Pt 10):2135-2140.
[8]Ferrari R,Rizzo P.The Notch pathway:A novel target for myocardial remodelling therapy?[J].Eur Heart J,2014,35(32):2140-2145.
[9]颜君,郭安源,贾海波,等.HEY转录因子的研究进展[J].现代生物医学进展,2013,13(4):763-768.
[10]魏铭,王国栋,郑国旭,等.Notch1及其下游靶分子Hes1在肾细胞癌组织中的表达及其临床意义[J].细胞与分子免疫学杂志,2014,30(4):417-420.
[11]Carew RM,Wang B,Kantharidis P.The role of EMT in renal fibrosis[J].Cell Tissue Res,2012,347(1):103-116.
[12]Adhikary A,Chakraborty S,Mazumdar M,et al.Inhibition of epithelial to mesenchymal transition by E-cadherin up-regulation via repression of slug transcription and inhibition of E-cadherin degradation:Dual role of scaffold/matrix attachment region-binding protein 1(SMAR1)in breast cancer cells[J].J Biol Chem,2014,289(37):25431-25444.
[13]赵文冰,孔心涓,姜英俊,等.Notch通路及Snail在大鼠肝纤维化发生发展中的作用[J].齐鲁医学杂志,2014,29(1):22-25.
[14]Kaufhold S,Bonavida B.Central role of Snail1 in the regulation of EMT and resistance in cancer:A target for therapeutic intervention[J].J Exp Clin Cancer Res,2014,33:62.
[15]Zavadil J,Cermak L,Soto-Nieves N,et al.Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition[J].EMBO J,2004,23(5):1155-1165.
[16]Aoyagi-Ikeda K,Maeno T,Matsui H,et al.Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway[J].Am J Respir Cell Mol Biol,2011,45(1):136-144.
[17]孙彬.Notch1/Jagged1在肾间质纤维化发病机制中的作用及干预的研究[D].南京:南京医科大学,2005.
[18]Morrissey J,Guo G,Moridaira K,et al.Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease[J].J Am Soc Nephrol,2002,13(6):1499-1508.
[19]张凯,艾文兵,柳长柏,等.Notch信号通路与HSC活化关系的研究进展[J].世界华人消化杂志,2013,21(33):3611-3616.
[20]Blokzijl A,Dahlqvist C,Reissmann E.Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3[J].J Cell Biol,2003,163(4):723-728.
[21]Bielesz B,Sirin Y,Si H,et al.Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans[J].J Clin Invest,2010,120(11):4040-4054.
[22]Phanish MK,Wahab NA,Colville-Nash P,et al.The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1responses in human proximal-tubule epithelial cells[J].Biochem J,2006,393(Pt 2):601-607.
[23]刘晗,王玲莉,程剑剑,等.γ-分泌酶抑制剂对大鼠肾小管上皮细胞间充质转分化的抑制作用[J].中华实验外科杂志,2014,31(4):805-807.
[24]Nyhan KC,Faherty N,Murray G,et al.Jagged/Notch signalling is required for a subset of TGFβ1 responses in human kidney epithelial cells[J].Biochim Biophys Acta,2010,1803(12):1386-1395.
[25]Saad S,Stanners SR,Yong R,et al.Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor[J].Int J Biochem Cell Biol,2010,42(7):1155-1122.
[26]Matsuno Y,Coelho AL,Jarai G,et al.Notch signaling mediates TGF-β1-induced epithelial-mesenchymal transition through the induction of Snai1[J].Int J Biochem Cell Biol,2012,44(5):776-789.
[27]朱天琦,吴晓娟,陈绪勇,等.Notch信号通路联合Wnt信号通路在肾母细胞瘤发病机制中的作用[J].中华实验外科杂志,2016,33(10):2407-2409.
[28]Lin CL,Wang FS,Hsu YC,et al.Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy[J].Diabetes,2010,59(8):1915-1925.
[29]Chen YX,Weng ZH,Zhang SL.Notch3 regulates the activation of hepatic stellate cells[J].World J Gastroenterol,2012,18(12):1397-1403.
[30]Chen Y,Zheng S,Qi D,et al.Inhibition of Notch signaling by aγ-secretase inhibitor attenuates hepatic fibrosis in rats[J].PLo SOne,2012,7(10):e46512.
[31]Xie G,Karaca G,Swiderska-Syn M,et al.Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice[J].Hepatology,2013,58(5):1801-1813.
[32]Kavian N,Servettaz A,Mongaret C,et al.Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model[J].Arthritis Rheum,2010,62(11):3477-3487.
[33]于秀文,曾林祥.Notch1在肌成纤维细胞转化中的作用及表达变化[J].中国现代医学杂志,2016,26(15):60-64.
[34]Wang DT,Huang RH,Cheng X,et al.TanshinoneⅡA attenuates renal fibrosis and inflammation via altering expression of TGF-β/Smad and NF-κB signaling pathway in 5/6 nephrectomized rats[J].Int Immunopharmacol,2015,26(1):4-12.
[35]赵斐,秦英,高永红,等.丹参酮ⅡA对TGF-β1诱导的人肾小管上皮细胞增殖及Ⅰ型胶原分泌的影响[J].上海中医药杂志,2014,48(6):96-98.
[36]唐锦辉,占成业.丹参酮ⅡA对大鼠肾间质纤维化的抑制作用[J].内科急危重症杂志,2008,14(1):16-18.
[37]王俏,吴莘,曹征,等.丹参酮ⅡA对糖尿病肾病大鼠肾组织氧化应激的影响[J/CD].中华临床医师杂志(电子版),2015,9(7):1149-1151.
[38]吕彦洁,孙建平,高延霞,等.丹参酮ⅡA磺酸钠对大鼠肾间质纤维化的影响及机制探讨[J].山东医药,2014,54(10):30-32.
[39]周儒兵,刘明华,何海霞.丹参酮ⅡA磺酸钠注射液对糖尿病大鼠肾脏的保护作用[J].中国药业,2008,17(13):7-8.
[40]唐云海,朱春玲.波形蛋白在大鼠肾间质纤维化中的表达及意义[J].贵州医科大学学报,2010,35(2):160-163.
[41]贺环宇.丹参酮ⅡA对大鼠肺间质纤维化的保护作用及机制研究[D].大连:大连医科大学,2014.
[42]张翼宙,卢冬冬,董颖,等.丹参酮ⅡA对大鼠肝纤维化的干预作用及其调控AngⅡ的分子机制[J].浙江中医药大学学报,2017,41(1):1-10.
[43]冯俊,李树生,屠恩远.丹参酮ⅡA通过下调CTGF抗血管紧张素Ⅱ诱导的心肌成纤维细胞Ⅰ型、Ⅲ型胶原合成[J].中国中医急症,2012,21(4):560-561,573.
[44]冯定浩.丹参酮ⅡA配伍DAPT对UUO模型大鼠肾组织NICD和Rbp-Jk蛋白表达的影响[D].遵义:遵义医学院,2018.
[45]徐静雅,李均,付旭.丹参酮ⅡA配伍DAPT对UUO大鼠肾间质纤维化的影响[J].遵义医学院学报,2018,41(5):562-568.
[46]何琼笑,赵峻峰.丹参酮ⅡA对缺血再灌注大鼠心肌Notch信号通路的影响[J].中华中医药学刊,2017,37(7):1840-1843.
[2]Leask A.Targeting the jagged/notch pathway:A new treatment for fibrosis?[J].J Cell Commun Signal,2010,4(4):197-198.
[3]Xiao Z,Zhang J,Peng X,et al.The Notchγ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation[J].Int J Biochem Cell Biol,2014,55:65-71.
[4]Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:Cell fate control and signal integration in development[J].Science,1999,284(5415):770-776.
[5]Grieselhuber NR,Klco JM,Verdoni AM,et al.Notch signaling in acute promyelocytic leukemia[J].Leukemia,2013,27(7):1548-1557.
[6]Schwanbeck R,Martini S,Bernoth K,et al.The Notch signaling pathway:Molecular basis of cell context dependency[J].Eur JCell Biol,2011,90(6/7):572-581.
[7]Hori K,Sen A,Artavanis-Tsakonas S.Notch signaling at a glance[J].J Cell Sci,2013,126(Pt 10):2135-2140.
[8]Ferrari R,Rizzo P.The Notch pathway:A novel target for myocardial remodelling therapy?[J].Eur Heart J,2014,35(32):2140-2145.
[9]颜君,郭安源,贾海波,等.HEY转录因子的研究进展[J].现代生物医学进展,2013,13(4):763-768.
[10]魏铭,王国栋,郑国旭,等.Notch1及其下游靶分子Hes1在肾细胞癌组织中的表达及其临床意义[J].细胞与分子免疫学杂志,2014,30(4):417-420.
[11]Carew RM,Wang B,Kantharidis P.The role of EMT in renal fibrosis[J].Cell Tissue Res,2012,347(1):103-116.
[12]Adhikary A,Chakraborty S,Mazumdar M,et al.Inhibition of epithelial to mesenchymal transition by E-cadherin up-regulation via repression of slug transcription and inhibition of E-cadherin degradation:Dual role of scaffold/matrix attachment region-binding protein 1(SMAR1)in breast cancer cells[J].J Biol Chem,2014,289(37):25431-25444.
[13]赵文冰,孔心涓,姜英俊,等.Notch通路及Snail在大鼠肝纤维化发生发展中的作用[J].齐鲁医学杂志,2014,29(1):22-25.
[14]Kaufhold S,Bonavida B.Central role of Snail1 in the regulation of EMT and resistance in cancer:A target for therapeutic intervention[J].J Exp Clin Cancer Res,2014,33:62.
[15]Zavadil J,Cermak L,Soto-Nieves N,et al.Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition[J].EMBO J,2004,23(5):1155-1165.
[16]Aoyagi-Ikeda K,Maeno T,Matsui H,et al.Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway[J].Am J Respir Cell Mol Biol,2011,45(1):136-144.
[17]孙彬.Notch1/Jagged1在肾间质纤维化发病机制中的作用及干预的研究[D].南京:南京医科大学,2005.
[18]Morrissey J,Guo G,Moridaira K,et al.Transforming growth factor-beta induces renal epithelial jagged-1 expression in fibrotic disease[J].J Am Soc Nephrol,2002,13(6):1499-1508.
[19]张凯,艾文兵,柳长柏,等.Notch信号通路与HSC活化关系的研究进展[J].世界华人消化杂志,2013,21(33):3611-3616.
[20]Blokzijl A,Dahlqvist C,Reissmann E.Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3[J].J Cell Biol,2003,163(4):723-728.
[21]Bielesz B,Sirin Y,Si H,et al.Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans[J].J Clin Invest,2010,120(11):4040-4054.
[22]Phanish MK,Wahab NA,Colville-Nash P,et al.The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1responses in human proximal-tubule epithelial cells[J].Biochem J,2006,393(Pt 2):601-607.
[23]刘晗,王玲莉,程剑剑,等.γ-分泌酶抑制剂对大鼠肾小管上皮细胞间充质转分化的抑制作用[J].中华实验外科杂志,2014,31(4):805-807.
[24]Nyhan KC,Faherty N,Murray G,et al.Jagged/Notch signalling is required for a subset of TGFβ1 responses in human kidney epithelial cells[J].Biochim Biophys Acta,2010,1803(12):1386-1395.
[25]Saad S,Stanners SR,Yong R,et al.Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor[J].Int J Biochem Cell Biol,2010,42(7):1155-1122.
[26]Matsuno Y,Coelho AL,Jarai G,et al.Notch signaling mediates TGF-β1-induced epithelial-mesenchymal transition through the induction of Snai1[J].Int J Biochem Cell Biol,2012,44(5):776-789.
[27]朱天琦,吴晓娟,陈绪勇,等.Notch信号通路联合Wnt信号通路在肾母细胞瘤发病机制中的作用[J].中华实验外科杂志,2016,33(10):2407-2409.
[28]Lin CL,Wang FS,Hsu YC,et al.Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy[J].Diabetes,2010,59(8):1915-1925.
[29]Chen YX,Weng ZH,Zhang SL.Notch3 regulates the activation of hepatic stellate cells[J].World J Gastroenterol,2012,18(12):1397-1403.
[30]Chen Y,Zheng S,Qi D,et al.Inhibition of Notch signaling by aγ-secretase inhibitor attenuates hepatic fibrosis in rats[J].PLo SOne,2012,7(10):e46512.
[31]Xie G,Karaca G,Swiderska-Syn M,et al.Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice[J].Hepatology,2013,58(5):1801-1813.
[32]Kavian N,Servettaz A,Mongaret C,et al.Targeting ADAM-17/notch signaling abrogates the development of systemic sclerosis in a murine model[J].Arthritis Rheum,2010,62(11):3477-3487.
[33]于秀文,曾林祥.Notch1在肌成纤维细胞转化中的作用及表达变化[J].中国现代医学杂志,2016,26(15):60-64.
[34]Wang DT,Huang RH,Cheng X,et al.TanshinoneⅡA attenuates renal fibrosis and inflammation via altering expression of TGF-β/Smad and NF-κB signaling pathway in 5/6 nephrectomized rats[J].Int Immunopharmacol,2015,26(1):4-12.
[35]赵斐,秦英,高永红,等.丹参酮ⅡA对TGF-β1诱导的人肾小管上皮细胞增殖及Ⅰ型胶原分泌的影响[J].上海中医药杂志,2014,48(6):96-98.
[36]唐锦辉,占成业.丹参酮ⅡA对大鼠肾间质纤维化的抑制作用[J].内科急危重症杂志,2008,14(1):16-18.
[37]王俏,吴莘,曹征,等.丹参酮ⅡA对糖尿病肾病大鼠肾组织氧化应激的影响[J/CD].中华临床医师杂志(电子版),2015,9(7):1149-1151.
[38]吕彦洁,孙建平,高延霞,等.丹参酮ⅡA磺酸钠对大鼠肾间质纤维化的影响及机制探讨[J].山东医药,2014,54(10):30-32.
[39]周儒兵,刘明华,何海霞.丹参酮ⅡA磺酸钠注射液对糖尿病大鼠肾脏的保护作用[J].中国药业,2008,17(13):7-8.
[40]唐云海,朱春玲.波形蛋白在大鼠肾间质纤维化中的表达及意义[J].贵州医科大学学报,2010,35(2):160-163.
[41]贺环宇.丹参酮ⅡA对大鼠肺间质纤维化的保护作用及机制研究[D].大连:大连医科大学,2014.
[42]张翼宙,卢冬冬,董颖,等.丹参酮ⅡA对大鼠肝纤维化的干预作用及其调控AngⅡ的分子机制[J].浙江中医药大学学报,2017,41(1):1-10.
[43]冯俊,李树生,屠恩远.丹参酮ⅡA通过下调CTGF抗血管紧张素Ⅱ诱导的心肌成纤维细胞Ⅰ型、Ⅲ型胶原合成[J].中国中医急症,2012,21(4):560-561,573.
[44]冯定浩.丹参酮ⅡA配伍DAPT对UUO模型大鼠肾组织NICD和Rbp-Jk蛋白表达的影响[D].遵义:遵义医学院,2018.
[45]徐静雅,李均,付旭.丹参酮ⅡA配伍DAPT对UUO大鼠肾间质纤维化的影响[J].遵义医学院学报,2018,41(5):562-568.
[46]何琼笑,赵峻峰.丹参酮ⅡA对缺血再灌注大鼠心肌Notch信号通路的影响[J].中华中医药学刊,2017,37(7):1840-1843.