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The decorin inhibiting TGFβ_1 induced renal tubular epithelial cell transdifferentiation signaling pathway research

Author: WangJinYa
Tutor: BaoHuaYing
School: Nanjing Medical University
Course: Pediatrics
Keywords: Decorin transdifferentiation renal tubular interstitialfibrosis transforming growth TGFβ1 renal tubular interstitial fibrosis transforming growth TGFβ1 Signal transduction
CLC: R692
Type: Master's thesis
Year: 2009
Downloads: 33
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Abstract


Glomerulosclerosis and tubulointerstitial fibrosis are common pathologica lfeatures of most end-stage kidneys. Recently years, tubulointerstitial fibrosis ismore important tha n glomerulosclerosis in end-stage kidneys, which has positivecorrela tion with aggravation of kidney function. Therefore, a many of scholareresstudy how precaution and treatment tubulointerstitial fibrosis. A large numberstudies suggested that rena l tubular epithelia l cells are not only victim but alsoinitiative participator in tubulointerstitial fibrosis.Many factors including ischemia,a noxia and some cytokines can inducedepithelium transdifferentiation . In this process, the cells lose their epithelia lcharacteristics, which includes their polarity ,specia lized cell-cell contacts andacquire a migratory behavior which allows them to move away from their epithelia lcell community and to integrate into surrounding tissue, secreteing interstitialcolla gens. There are studies suggesting that 36% fibroblasts come fromtransdifferentiation of rena l tubule epithelia l cells in tubulointerstitial fibrosis,therefore,the transdifferentiation of rena l tubule epithelia l cells pla y an importantrole in tubulointerstitial fibrosis. Transforming growth factorβ1 is one of keycytokines in inducing fibrosis, which can initiate and completed the process oftransdifferentiation, therefore, the key of treating tubulointerstitial fibrosis isseeking matters which can inhibite rena l tubule epithelia l transdifferentiationinduced by transforming growth factorβ1.Decorin is a sma ll leucine-rich extra cellular matrix proteoglyca n composedof a core protein with a single glycosa minoglycan （GAG） chain near the Nterminus.Metabolism disorders or formation changes of Decorin have the intimaterelation with pathologic process of kidney diseases. Its expression supportscapillary formation and cell survival, influences fibril stability, and interacts withextra cellular matrix molecules to influence cells adhesion. Increasing evidencesshow that Decorin pla ys an important role in fibrogenesis by regulating TGFβ1. It isnot only a factor of extra cellular matrix, but also a natural antagonist oftransforming growth factor and ma y accommoda te the process and dela y the development of rena l fibrosis induced by some cytokines, colla gen, fibroblasts,macropha ges, and so on. In order to illustrate the mecha nism between Decorin andTGFβ1, especia lly the effects of Decorin on the transdifferentiation in human rena ltubular epithelia l cells induced by TGFβ1 in vitro, we performed the following twopartstudy in vitro.ParPart 1 : Effect of Decorin on transdifferentiation inducedby transforming growth factorβ1 inRenal tubular epithelial cellsObjective：To observe the effects of Decorin on transforming growth factorβ1（TGFβ1）triggered tubular epithelia l epithelia l-mesenchymal transition （EMT）.Methods：Cultured HK-2 cells were divided into 4 groups:A. nega tive control ; B.100ng/mL Decorin; C.10 ng/mL TGFβ1；D.100 ng/mL Decorin and 10 ng/mL TGFβ1. Themorphology of transdifferentiate tubular cells was observed by using phase-contrastmicroscopy;RT-PCR and Western blot detected the expression of vimentin and Ecadherin.Results：In A group, B group, morphology of cells had no changes, the expressionsof vimentin and E-cadherin had no differences in these two groups. Compared to Agroups, C group ,HK-2 cells induced by TGFβ1 converted into spind le shape fromtypica l epithelium shape, the expression of vimentin significa nt increased , theexpression of E-cadherin significa nt decreased. Compared to C groups , D groups, theexpression of vimentin significa ntly decreased , the expression of E-cadherinsignifica ntly increased. Compared to A groups, D groups, the expression of vimentinstill increased and the expression of E-cadherin still decreased.Conclusion：Decorin could block EMT triggered by TGFβ1, which implies thatDecorin could participate in rena l interstitial fibrosis as a nega tive regulator. ParPart 2 : The Signal transduction of Decorin inhibitingtransdifferentiation induced by transforming growthfactorβ1 in renal tubular epithelial cellsObjective: To investigate the mecha nisms of Decorin on transdifferentiation （EMT）induced by transforming growth factorβ1（TGFβ1） in rena l tubular epithelia l cells .Methods: HK-2 cells in vitro were divided into 4 groups: A. nega tive control group;B. Decorin group, add Decorin 100ng/ml ; C. TGFβ1 group, add TGFβ110ng/ml；D.Decorin and TGFβ1group, add Decorin 100ng/ml and TGFβ1 10ng/ml. The proteinlevel of phosphor-ERK, phosphor- PI3K , phosphor- Smad 3 andβ-catenin wasdetected by Western blot method . The snail mRNA level was tested by rReal Time-PCR, while the Lymphoid Enhancer Factor-1（LEF1） mRNA level was measured byRT-PCR.Results: The protein level of phosphor-ERK, phosphor- PI3K , phosphor- Smad 3 andβ-catenin and the expressions of snail and LEF1 mRNA had no differences inbetween A group and B groups. Compared to A group, C group, the snail and LEF1mRNA were significa ntly up-regulated, mea nwhile the protein level of phosphor-ERK, phosphor- PI3K , phosphor- Smad 3 andβ-catenin were significa ntly increased .The phosphor-ERK protein level and the snail mRNA level were significa ntly downregulatedin D group compared to C group, however there were no statistica llysignifica nt differences in the level of phosphor- PI3K, phosphor- Smad 3 andβ-cateninbetween C group and D group.Conclusion: Decorin inhibit EMT induced by TGFβ1which ma y be through block ingthe ERK Signal transduction pathway.

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CLC: > Medicine, health > Surgery > Urology ( urinary and reproductive system diseases) > Kidney disease
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