整合素连接激酶(ILK)在肾脏疾病中的研究进展
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摘要
整合素连接激酶(integrin-linked kinase,ILK)是一种丝氨酸/苏氨酸蛋白激酶,可与整合素β1、β3亚基胞浆域结合,参与整合素、生长因子、Wnt及TGF-β/Smad等多种信号转导,在调节细胞黏附、凋亡、转移、生长、细胞周期、肿瘤形成等过程中起重要作用。细胞中ILK表达异常,将引发病理变化。本文综述了ILK的生物学活性及其与肾脏疾病的关系,提示ILK的表达调控可能成为治疗肾脏疾病的新途径。
Integrin-linked kinase(ILK) is a serine/threonine protein kinase, which interacts with the cytoplasmic domain of integrin β1 and β3 and participates in signal transduction such as integrin, growth factor, Wnt and TGF-beta/Smad. It plays an important role in the regulation of cell adhesion, apoptosis, metastasis, growth, cell cycle, tumor formation and so on. Abnormal expression of ILK in cells may lead to pathological changes. In this paper, the biological activity of ILK and its relationship with kidney diseases were summarized. These data suggest that the regulation of ILK expression may be a new approach for the treatment of renal diseases.
Integrin-linked kinase(ILK) is a serine/threonine protein kinase, which interacts with the cytoplasmic domain of integrin β1 and β3 and participates in signal transduction such as integrin, growth factor, Wnt and TGF-beta/Smad. It plays an important role in the regulation of cell adhesion, apoptosis, metastasis, growth, cell cycle, tumor formation and so on. Abnormal expression of ILK in cells may lead to pathological changes. In this paper, the biological activity of ILK and its relationship with kidney diseases were summarized. These data suggest that the regulation of ILK expression may be a new approach for the treatment of renal diseases.
引文
[1]OLMOS G,LOPEZ-ONGIL S,RUIZ TORRES M P.Integrinlinked kinase:A new actor in the ageing process?[J].Exp Gerontol,201(100):87-90.
[2]HANNIGAN G E,LEUNG-HAGESTEIJN C,FITZ-GIBBON L,et al.Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase[J].Nature,1996(379):91-96.
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[5]QI F,CAI P,LIU X,et al.Adenovirus-mediated P311 inhibits TGF-beta1-induced epithelial-mesenchymal transition in NRK-52E cells via TGF-beta1-Smad-ILK pathway[J].Biosci Trends,2015,9(5):299-306.
[6]秦明哲,张翥.中药影响整合素连接激酶在肾小管间质纤维化中表达的研究进展[J].临床医药文献杂志,2016,3(16):3328-3329.
[7]PENG L,YANG J,NING C,et al.Rhein inhibits integrin-linked kinase expression and regulates matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1ratio in high glucose-induced epithelial-mesenchymal transition of renal tubular cell[J].Biol Pharm Bull,2012,35(10):1676-85.
[8]ZHOU W,CAO H,YANG X,et al.Characterization of nuclear localization signal in the N terminus of integrin-linked kinase-associated phosphatase(ILKAP)and its essential role in the down-regulation of RSK2 protein signaling[J].J Biol Chem,2013,288(9):6259-6271.
[9]MCDONALD P C,FIELDING A B,DEDHAR S.Integrinlinked kinase-essential roles in physiology and cancer biology[J].J Cell Sci,2008,121(Pt 19):3121-3132.
[10]GUO L,SANDERS P W,WOODS A,et al.The distribution and regulation of integrin-linked kinase in normal and diabetic kidneys[J].Am J Pathol,2001,159(5):1735-1742.
[11]LI Y,YANG J,DAI C,et al.Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis[J].J Clin Invest,2003,112(4):503-516.
[12]LIN Z F,JIA L,ZHAO D,et al.Effect of integrin-linked kinase inhibitor QLT0267 on tubular epithelial-myofibroblast transdifferentiation of HK-2 cells[J].China J Mod Med(中国现代医学杂志),2016,26(17):39-44.
[13]LI Y W,WU H G,SHI Y.Role of Snail in regulation of intestinal epithelial mesenchymal transition[J].World J Gastroenterol(世界华人消化杂志),2016,26(1):81-88.
[14]SHIMIZU M,KONDO S,URUSHIHARA M,et al.Role of integrin-linked kinase in epithelial-mesenchymal transition in crescent formation of experimental glomerulonephritis[J].Nephrol Dial Transplant,2006,21(9):2380-2390.
[15]LI X B,PENG B Y,YANG J Q,et al.Effects of Persicae Semen and safflower on the expressions of ILK,E-cad,FN andα-SMA in the renal tissue of unilateral ureteral obstruction rats[J].J Zunyi Med Univ(遵义医学院学报),2017,40(2):134-138.
[16]LIU B C,LI M X,ZHANG J D,et al.Inhibition of integrin-linked kinase via a si RNA expression plasmid attenuates connective tissue growth factor-induced human proximal tubular epithelial cells to mesenchymal transition[J].Am J Nephrol,2008,28(1):143-151.
[17]HE D G,YANG X P.Expression of integrin-linked kinase in rat model of adriamycin nephrosis[J].Guide China Med(中国医药指南),2014,12(34):5-7.
[18]NIU H L,NIE L,LIU M D,et al.Benazepril affects integrin-linked kinase and smooth muscle alpha-actin expression in diabetic rat glomerulus and cultured mesangial cells[J].BMC Nephrol,2014(15):135.
[19]DU M,WANG Q,LI W,et al.Overexpression of FOXO1ameliorates the podocyte epithelial-mesenchymal transition induced by high glucose in vitro and in vivo[J].Biochem Biophys Res Commun,2016,471(4):416-422.
[20]RAMAN A,REIF G A,DAI Y,et al.Integrin-linked kinase signaling promotes cyst growth and fibrosis in polycystic kidney disease[J].J Am Soc Nephrol,2017,28(9):2708-2719.
[21]WU P A,LI S S,TANG Q L,et al.Clinical significance of integrin-linked kinase in laryngeal squamous cell carcinoma[J].Auris Nasus Larynx,2017,44(4):458-463.
[22]HAN K S,LI N,RAVEN P A,et al.targeting integrin-linked kinase suppresses invasion and metastasis through downregulation of epithelial-to-mesenchymal transition in renal cell carcinoma[J].Mol Cancer Ther,2015,14(4):1024-1034.
[23]HANNIGAN G,TROUSSARD A A,DEDHAR S.Integrin-linked kinase:a cancer therapeutic target unique among its ILK[J].Nat Rev Cancer,2005,5(1):51-63.
[24]CANO-PENALVER J L,GRIERA M,GARCIA-JEREZ A,et al.Renal integrin-linked kinase depletion induces kidney c GMP axis upregulation:Consequences on basal and acutely damaged renal function[J].Mol Med,2015,21(1):873-885.
[25]HATEM-VAQUERO M,GRIERA M,GIERMAKOWSKA W,et al.Integrin linked kinase regulates the transcription of AQP2 by NFATC3[J].Biochim Biophys Acta,2017,1860(9):922-935.
[2]HANNIGAN G E,LEUNG-HAGESTEIJN C,FITZ-GIBBON L,et al.Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase[J].Nature,1996(379):91-96.
[3]MCDONALD P C,FIELDING A B,DEDHAR S.Integrinlinked kinase-essential roles in physiology and cancer biology[J].J Cell Sci,2008,121(Pt 19):3121-3132.
[4]LI J J,LIU Y,ZHAO J,et al.Transplantation of cardiac stem cells overexpressing integrin-linked kinase improves cardiac function in a rat model of acute myocardial infarction[J].Chin J Cardiol(中华心血管病杂志),2017,45(10):880-886.
[5]QI F,CAI P,LIU X,et al.Adenovirus-mediated P311 inhibits TGF-beta1-induced epithelial-mesenchymal transition in NRK-52E cells via TGF-beta1-Smad-ILK pathway[J].Biosci Trends,2015,9(5):299-306.
[6]秦明哲,张翥.中药影响整合素连接激酶在肾小管间质纤维化中表达的研究进展[J].临床医药文献杂志,2016,3(16):3328-3329.
[7]PENG L,YANG J,NING C,et al.Rhein inhibits integrin-linked kinase expression and regulates matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1ratio in high glucose-induced epithelial-mesenchymal transition of renal tubular cell[J].Biol Pharm Bull,2012,35(10):1676-85.
[8]ZHOU W,CAO H,YANG X,et al.Characterization of nuclear localization signal in the N terminus of integrin-linked kinase-associated phosphatase(ILKAP)and its essential role in the down-regulation of RSK2 protein signaling[J].J Biol Chem,2013,288(9):6259-6271.
[9]MCDONALD P C,FIELDING A B,DEDHAR S.Integrinlinked kinase-essential roles in physiology and cancer biology[J].J Cell Sci,2008,121(Pt 19):3121-3132.
[10]GUO L,SANDERS P W,WOODS A,et al.The distribution and regulation of integrin-linked kinase in normal and diabetic kidneys[J].Am J Pathol,2001,159(5):1735-1742.
[11]LI Y,YANG J,DAI C,et al.Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis[J].J Clin Invest,2003,112(4):503-516.
[12]LIN Z F,JIA L,ZHAO D,et al.Effect of integrin-linked kinase inhibitor QLT0267 on tubular epithelial-myofibroblast transdifferentiation of HK-2 cells[J].China J Mod Med(中国现代医学杂志),2016,26(17):39-44.
[13]LI Y W,WU H G,SHI Y.Role of Snail in regulation of intestinal epithelial mesenchymal transition[J].World J Gastroenterol(世界华人消化杂志),2016,26(1):81-88.
[14]SHIMIZU M,KONDO S,URUSHIHARA M,et al.Role of integrin-linked kinase in epithelial-mesenchymal transition in crescent formation of experimental glomerulonephritis[J].Nephrol Dial Transplant,2006,21(9):2380-2390.
[15]LI X B,PENG B Y,YANG J Q,et al.Effects of Persicae Semen and safflower on the expressions of ILK,E-cad,FN andα-SMA in the renal tissue of unilateral ureteral obstruction rats[J].J Zunyi Med Univ(遵义医学院学报),2017,40(2):134-138.
[16]LIU B C,LI M X,ZHANG J D,et al.Inhibition of integrin-linked kinase via a si RNA expression plasmid attenuates connective tissue growth factor-induced human proximal tubular epithelial cells to mesenchymal transition[J].Am J Nephrol,2008,28(1):143-151.
[17]HE D G,YANG X P.Expression of integrin-linked kinase in rat model of adriamycin nephrosis[J].Guide China Med(中国医药指南),2014,12(34):5-7.
[18]NIU H L,NIE L,LIU M D,et al.Benazepril affects integrin-linked kinase and smooth muscle alpha-actin expression in diabetic rat glomerulus and cultured mesangial cells[J].BMC Nephrol,2014(15):135.
[19]DU M,WANG Q,LI W,et al.Overexpression of FOXO1ameliorates the podocyte epithelial-mesenchymal transition induced by high glucose in vitro and in vivo[J].Biochem Biophys Res Commun,2016,471(4):416-422.
[20]RAMAN A,REIF G A,DAI Y,et al.Integrin-linked kinase signaling promotes cyst growth and fibrosis in polycystic kidney disease[J].J Am Soc Nephrol,2017,28(9):2708-2719.
[21]WU P A,LI S S,TANG Q L,et al.Clinical significance of integrin-linked kinase in laryngeal squamous cell carcinoma[J].Auris Nasus Larynx,2017,44(4):458-463.
[22]HAN K S,LI N,RAVEN P A,et al.targeting integrin-linked kinase suppresses invasion and metastasis through downregulation of epithelial-to-mesenchymal transition in renal cell carcinoma[J].Mol Cancer Ther,2015,14(4):1024-1034.
[23]HANNIGAN G,TROUSSARD A A,DEDHAR S.Integrin-linked kinase:a cancer therapeutic target unique among its ILK[J].Nat Rev Cancer,2005,5(1):51-63.
[24]CANO-PENALVER J L,GRIERA M,GARCIA-JEREZ A,et al.Renal integrin-linked kinase depletion induces kidney c GMP axis upregulation:Consequences on basal and acutely damaged renal function[J].Mol Med,2015,21(1):873-885.
[25]HATEM-VAQUERO M,GRIERA M,GIERMAKOWSKA W,et al.Integrin linked kinase regulates the transcription of AQP2 by NFATC3[J].Biochim Biophys Acta,2017,1860(9):922-935.