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|Title: ||Endothelial mesenchymal transition in kidney fibrosis, and the role of MMP-9 dependent Notch signaling|
|Authors: ||Zhao, Ye|
|Issue Date: ||18-Dec-2014|
|Publisher: ||University of Sydney|
Sydney Medicine School
|Abstract: ||Endothelial-mesenchymal transition (EndoMT) has been shown to be a major source of myofibroblast formation in kidney fibrosis. This study investigated whether Notch signaling plays a role in MMP-9-induced EndoMT of kidney endothelial cells in kidney. Mouse kidney peritubular endothelial cells (MKPEC) were isolated and co-cultured with tubular epithelial cell. MKPECs and human kidney glomerular endothelial cells (HKGECs) were treated with TGF-β1 or recombinant human MMP-9 (rhMMP-9) to induce EndoMT. EndoMT was assessed by immunofluorescence staining and Western blot (WB). Notch signaling was examined by WB. MMP-9 expression was examined by zymography. Interstitial fibrosis was assessed by Trichrome stain. EndoMT was evidenced by significant downregulation of VE-cadherin & CD31 and upregulation of α-SMA. Inhibition of MMP-9 or Notch signaling by their inhibitors demonstrated a dose-dependent response in preventing EndoMT. MMP-9 deficiency also led to a significant reduction in EndoMT in MKPECs. MMP-9 KO mice with UUO showed a significant reduction of interstitial fibrosis, α-SMA expression and fibroblasts originating via EndoMT. These findings demonstrate an important role for MMP-9 in causing kidney fibrosis, especially through the induction of EndoMT in different types of endothelial cells, and highlight the importance of the relationship between MMP-9 and the Notch signaling pathway.|
|Access Level: ||Access is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.|
|Rights and Permissions: ||The author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (University of Sydney Access only)|
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|ZHAO Ye - Final Thesis.pdf||Thesis||6.03 MB||Adobe PDF|
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