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Kidney Week

Abstract: TH-OR011

The Hyaluronan Synthase-1 Isoenzyme Promotes Differentiation to a Distinct Subset of Myofibroblasts That Limit Fibrosis Progression

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Williams, Aled P., Wales Kidney Research Unit, Cardiff, United Kingdom
  • Midgley, Adam C., Nankai University, Tianjin, China
  • Brown, Charlotte Victoria Maynard, Wales Kidney Research Unit, Cardiff, United Kingdom
  • Roberts, Talea Hope, Wales Kidney Research Unit, Cardiff, United Kingdom
  • Morris, Nathanael Glyn, Wales Kidney Research Unit, Cardiff, United Kingdom
  • Steadman, Robert, Wales Kidney Research Unit, Cardiff, United Kingdom
  • Phillips, Aled O., Wales Kidney Research Unit, Cardiff, United Kingdom
  • Meran, Soma, Wales Kidney Research Unit, Cardiff, United Kingdom
Background

Renal interstitial fibrosis is a key determinant of CKD progression, and increased synthesis of the glycosaminoglycan, Hyaluronan (HA), in renal tissue correlates with fibrosis and renal outcomes. Factors that regulate HA synthesis therefore influence CKD progression. HA is synthesized by three HA Synthase enzymes (HAS1, HAS2 and HAS3). Our work has specifically shown that increased HAS2 expression is causally linked with fibrosis in vivo and is a critical mediator of pro-fibrotic cell phenotype in vitro. Furthermore, the anti-fibrotic growth factor BMP7 (Bone Morphogenetic Protein-7) prevents/reverses pro-fibrotic cell phenotype and renal fibrosis in murine models. Recent data shows BMP7 significantly increases HAS1 expression, indicating a possible protective role for this enzyme in fibrosis

Methods

Studies were performed on human proximal tubular epithelial cells our established library of scarring versus non-scarring primary fibroblasts. Genetic and histological analysis of kidneys from HAS1, HAS3 and HAS1/3 double knockout mice and Ischaemia Reperfusion Injury (IRI) -induced renal fibrosis were used

Results

In response to TGF-β1, cells primarily expressing the HAS2 isoenzyme assembled large pericellular HA coats tethered to the principal HA receptor CD44-standard. The cells were significantly α-smooth muscle actin (αSMA) positive and had a contractile phenotype. TGF-β1 stimulation in HAS1 isoenzyme expressing cells had negligible HA pericellular coats and enhanced cell-surface expression of the CD44 variant isoform, CD44v7/8. These cells had a limited contractile response, were pro-migratory, with low αSMA expression and laid down different matrix. Mice with IRI have elevated levels of both HAS1 and HAS2 in acute early injury, and HAS2 in late injury; whilst kidneys from HAS1/3 DKO mice were predisposed to pro-fibrotic renal injury

Conclusion

Different HAS isoenzymes have distinct and likely conflicting roles in response to pro-fibrotic stimuli. Whilst HAS2 promotes a pro-fibrotic contractile cell phenotype associated with tissue fibrosis, HAS1 appears to limit pro-fibrotic phenotypes and promotes a distinct subset of myofibroblasts that are pro-migratory and may be involved in reparative processes that limits fibrotic injury