Relevant Key Words:

hyaluronan synthases, gene expression, extracellular matrix, renal fibrosis

Research Expertise relevant to tissue engineering & repair:

A variety of kidney disorders lead to renal fibrosis and then end stage renal disease (ESRD), resulting in inadequate kidney function and the need for dialysis treatment or transplantation. In the kidney, the onset of ESRD is almost always accompanied by a pronounced expansion of the extracellular matrix (ECM). We wish to understand the mechanisms by which this increase in ECM production occurs and then to investigate potential therapeutic steps to combat kidney disease.

The synthesis of the key ECM glycosaminoglycan hyaluronan (HA) increases significantly during renal matrix expansion. HA is synthesised by the family of proteins called the hyaluronan synthase (HAS) enzymes, comprising HAS1, HAS2 and HAS3. The HASs span the cell membrane and nascent HA chains are extruded directly into the ECM. Our investigation into the regulation of HA synthesis in the kidney has started with analysis of the transcriptional regulation of the HAS genes, which encode the HAS enzymes, in cultured renal proximal tubular epithelial cells.

We have located and analysed putative promoter regions for each HAS gene and have so far looked in detail at the HAS2 promoter. The HAS2 gene is up-regulated in elevated glucose conditions that mimic diabetic nephropathy and also in response to stimulation by the key fibrotic mediator TGF-b1 and the pro-inflammatory cytokine IL-1 b.

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