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《Journal of Third Military Medical University》 2012-19
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GSK3β plays pro-fibrogenic activity through TGF-beta/Smad signaling pathway in renal tubular epithelial cells

Zhao Kai1,2,Chen Shan1,Gong Rujun3,Li Song4,He Fengtian1(1Department of Biochemistry and Molecular Biology,2Department of Pathogenic Biology,College of Basic Medical Sciences,Third Military Medical University,Chongqing,400038,China;3Division of Kidney Disease and Hypertension,Brown University School of Medicine,Providence,Rhode Island 02903,USA;4School of Pharmacy,University of Pittsburgh,Pittsburgh,PA15261,USA)  
Objective To address whether glycogen synthase kinase-3 beta(GSK3β)plays direct roles in renal fibrosis based on our previous study that expression of GSK3β is substantially increased in transplanted human kidney with chronic allograft nephropathy and valproate markedly ameliorates renal fibrosis in rats with unilateral urethral obstruction.Methods A standard in vitro model of interstitial fibrosis,cultured human tubular epithelial(HK-2) cells treated with TGF-β1,was examined in our experiments.A selective GSK3β inhibitor,LiCl was used to suppress the activity of GSK3β.The eukaryotic expression vectors encoding HA-tagged wild type(WT-GSK3β-HA/pcDNA3.1),uninhibitable mutant GSK3β(S9A-GSK3β-HA/pcDNA3.1) and kinase dead mutant GSK3β(K85,86A-GSK3β-HA/pcDNA3.1) were transfected in HK-2 cells respectively.Results LiCl increased the phosphorylation of GSK3β,and suppressed both the basal and TGF-β1 induced fibronectin(FN) expression in HK-2 cells.When transfected with expression vector encoding wild type GSK3β or an mutant GSK3β S9A,HK-2 cells displayed increased FN expression;whereas decreased FN expression was observed when transfected vector encoding GSK3β K85A,K86A.To further analyze the possible pathway that GSK3β regulated fibrosis,it was found that in LiCl treated HK-2 cells,phosphorylation of Smad3 was suppressed.While there was no change observed for the phosphorylation level of Smad2.Conclusion In summary,our results suggest that TGF-β/Smad3 pathway can be regulated by GSK3β,and therefore GSK3β plays pro-fibrogenic activity in renal tubular epithelial cells.
【Fund】: 国家自然科学基金(30900766 81228005);; 重庆市自然科学基金(CSTC2011BB5025)~~
【CateGory Index】: R692
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1 CHEN Xi-ming 1,LI Yun-he 2,HOU Jian-hui 1,LIU Yu-jun 1,YE Bo-ran 1,HUANG Zhao-qi 1,CHEN Shengqiang 3,HUANG Qing-hui 4,HUANG Wen-hui 5(1.The Third Affiliated Hospital of Guangzhou Medical University,Guangzhou 510150,China;2.Sun Yat_Sen University Cancer Center,Guangzhou 510080,China;3.The Second Affiliated Hospital of Guangzhou Medical University,Guangzhou 510260,China;4.The First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China;5.Guangdong Cardiovascular Institute,Guangdong General Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China);Expression of hippocampus of glycogen synthase kinase-3β and transforming growth factor-β1 in rats with chronic heart failure[J];South China Journal of Cardiovascular Diseases;2013-04
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