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Effect of Decorin on Epithelial-To-Mesenchymal Transition and Fibrogenesis in Human Peritoneal Mesothelial Cells

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Effect of Decorin on Epithelial-To-Mesenchymal Transition and Fibrogenesis in Human Peritoneal Mesothelial Cells

Implications in Peritoneal Dialysis

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Effect of Decorin on Epithelial-To-Mesenchymal Transition and Fibrogenesis in Human Peritoneal Mesothelial Cells by Na Jiang
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This dissertation, "Effect of Decorin on Epithelial-to-mesenchymal Transition and Fibrogenesis in Human Peritoneal Mesothelial Cells: Implications in Peritoneal Dialysis" by Na, Jiang, 姜娜, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Effect of Decorin on Epithelial-to-mesenchymal Transition and Fibrogenesis in Human Peritoneal Mesothelial Cells: Implications in Peritoneal Dialysis Submitted by Na JIANG for the degree of Doctor of Philosophy at The University of Hong Kong in October 2015 Peritoneal dialysis (PD) is an established renal replacement therapy that utilizes the patient's peritoneum as a dialyzing organ. Long-term exposure to peritoneal dialysates and episodes of peritonitis lead to structural and functional deterioration of the peritoneum. Mesothelial cells cover the surface of the peritoneum and are the first line of defense against chemical or bacterial insult. Changes in mesothelial cell function often precede peritoneal fibrosis and failure to serve its dialytic function. Decorin is a dermatan sulfate proteoglycan that has anti-fibrotic properties. It is the predominant proteoglycan secreted by human peritoneal mesothelial cells (HPMC). The research hypothesis of this project is that decorin affects HPMC functions related to inflammation and fibrosis, and may be beneficial in the preservation of normal HPMC functions in the setting of PD associated peritonitis. The level of decorin in peritoneal dialysate of PD patients with or without peritonitis was investigated. The relationship between decorin and biomarkers for inflammation and fibrosis and also peritoneal transport parameters were examined. Experiments were performed to investigate the effect of effluent peritoneal dialysate on HPMC phenotypic changes and its expression of markers of inflammation, epithelial-to-mesenchymal transition (EMT) and fibrosis, and to investigate the role of decorin in these processes. Results from experiments showed increased dialysate decorin level during peritonitis, which peaked at three days after onset and remained elevated three months later despite clinical resolution of peritonitis. Dialysate decorin level correlated with dialysate levels of TGF-1 and peritoneal transport rate, and inversely correlated with IL-1, IL-6, IL-8 and HGF levels, white blood cell count in dialysate, residual renal function, and urine output. Under physiological conditions, cultured HPMC formed a homogeneous monolayer with polygonal epithelial morphology, expressing E-cadherin, collagen III, and low levels of SNAIL, -smooth muscle actin and fibronectin. Exposure of HPMC to PD fluid (PDF) obtained during peritonitis for 24 h decreased E-cadherin expression, accompanied by a loss of cell-cell contact and an elongated phenotype, with induction of SNAIL, -smooth muscle actin and fibronectin expression, which were mediated in part through activation of ERK, p38 MAPK, JNK and PI3K signaling pathways. These changes were attributed in part to increased TGF-1 and IL-1 levels in PDF during peritonitis. Decorin (1g/ml) partially suppressed the induction of EMT and fibrogenic mediators by PDF, and this effect was associated with reduction of p38 MAPK and PI3K activation and increased GSK-3 phosphorylation. Gene silencing studies confirmed the anti-fibrotic effect of decorin. Knockdown of decorin was accompanied by reduced IL-1-mediated induction of IL-6, IL-8 and MCP-1 secretion. In summary, the data demonstrated the ameliorating effect of decorin on HPMC EMT and the p
Release date NZ
January 26th, 2017
Author
Contributor
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Country of Publication
United States
Illustrations
colour illustrations
Imprint
Open Dissertation Press
Dimensions
216x279x16
ISBN-13
9781361041147
Product ID
26646295

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