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Bommayya, Girish
Languages: English
Types: Doctoral thesis
Subjects: R1
Epithelial mesenchymal transdifferentiation (EMT) has been shown to contribute to renal disease and tissue fibrosis and is known to be mediated by transforming growth factor-β (TGF-β). EMT involves loss of an epithelial phenotype and acquisition of a mesenchymal or myofibroblastic phenotype shown by up-regulation of α-smooth muscle actin (α-SMA). Assembly of hyaluronan (HA) has an important role in extracellular matrix formation and in maintaining the phenotype of different cells. HA has been shown to organize into cable structures or peri-cellular coats. Cable HA binds to inflammatory proteins and prevents their cell surface interaction and has anti-inflammatory properties, while peri-cellular coats make cells migratory. HA assembly is influenced by its interaction with hyaladherins and this study investigated the role of tumour necrosis factor-α stimulated gene (TSG)-6, one of the hyaladherins by assessing its interaction with HA, HABP and CD44 in proximal tubular cells (PTC) EMT. \ud TSG-6 has an important role as an anti-inflammatory protein and is upregulated when stimulated with interleukin-1β (IL-1β) and TGF-β. In the presence of TGF-β, PTCs were demonstrated to be less migratory, with reduced E-cadherin and increased α-SMA expression suggesting TSG-6 may have important role in EMT. Both IL-1β and TGF-β induce increased expression of hyaluronan synthase (HAS) 2 and HA receptor, CD44. This also leads to loss of HA cables and increased assembly of an HA coat. \ud Knockdown of TSG-6 gene in PTC leads to loss of HA cables and the peri-cellular assembly of HA coat was loose and scattered. These TSG-6 knockdown PTCs maintained its epithelial phenotype and TGF-β-mediated phenotypic transition was blocked. There was increased expression of CD44 and HAS2 in these TSG-6 knockdown cells and in subsequent experiments where CD44 was silenced with transfection, HAS2 expression was inhibited. This suggests that HAS2 expression was dependent on CD44 in the absence of TSG-6. \ud These results collectively show that TSG-6 has an important role in EMT in PTCs.

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