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The human hyaluronan synthase 2 gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell and fibroblast

Altaher, Abdalsamed 2012. The human hyaluronan synthase 2 gene and its natural antisense RNA exhibit coordinated expression in the renal proximal tubular epithelial cell and fibroblast. MPhil Thesis, Cardiff University.
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Abstract

Previous research at the Institute of Nephrology (IoN) has focused on the role of the vertebrate extracellular matrix (ECM) glycosaminoglycan, hyaluronan (HA), in renal fibrosis. The most effective predictors of disease outcome are interstitial accumulation of myofibroblasts and associated ECM expansion. The function of HA in the differentiation of resident and/or infiltrating fibroblasts to myofibroblasts, or by epithelial-to-mesenchymal transition of renal proximal tubular epithelial cells (PTCs) to a myofibroblastic phenotype, is therefore of great interest. HA is synthesised by the HA synthase (HAS) enzymes, encoded by the corresponding HAS genes. Work at the IoN has shown HAS2 induction by fibrotic mediating cytokine transforming growth factor-β1 (TGF-β1) and pro-inflammatory cytokine interleukin-1 beta (IL-1β), and that HAS2 is the dominant HAS isoform in the regulation of fibroblast and PTC phenotype. Recent data from the IoN showed coordinated expression of HAS2 and its natural antisense RNA, HAS2-AS1, in TGF-β1- and IL-1β-treated PTCs. The work described in this thesis began with confirmation of these findings, and this cytokine-driven coordinated expression pattern was then demonstrated in primary fibroblasts. Forced expression of the HAS2 open reading frame in PTC induced up-regulated HAS2-AS1 transcription, while inhibition of HA synthesis down-regulated IL-1β- driven antisense up-regulation; HAS2 siRNA knockdown in PTC did not significantly change HAS2-AS1 expression. By contrast, and confirming previous IoN findings, siRNA knockdown of HAS2-AS1 expression also resulted in significant downregulation of HAS2 mRNA synthesis, while novel data showed that forced HAS2- AS1 expression had no significant effect on HAS2 transcription. In conclusion, TGF-β1 and IL-1β-driven coordinated expression of HAS2 and HAS2- AS1 was demonstrated for the first time in primary lung, oral mucosal, and dermal fibroblasts. Data from manipulation of HAS2 and HAS2-AS1 expression in PTC suggested that antisense transcription was regulated by HA-driven signalling, and that transcription of HAS2-AS1 antisense RNA stabilised and/or augmented HAS2 expression.

Item Type: Thesis (MPhil)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 30 March 2016
Last Modified: 19 Mar 2016 23:07
URI: https://orca.cardiff.ac.uk/id/eprint/39472

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