Hyaluronan synthase isoforms mark distinct fibroblast states in the kidney: HAS2 is associated with contractile profibrotic myofibroblasts and chronic fibrosis after ischaemia-reperfusion injury, whereas HAS1 is associated with migratory, FAP-expressing, less profibrotic stromal cells present during development and recovery.
In healthy adult kidneys, stromal HA is absent, HAS1 shows limited epithelial expression, and HAS2 is undetectable.
After renal ischaemia-reperfusion injury, stromal HA accumulation and increased HAS2 expression were associated with chronic fibrosis.
During kidney development, prominent stromal HA matrices were present in areas of tubular generation and were associated with strong HAS1, not HAS2, expression.
During recovery from injury, stromal HA and HAS2 were attenuated, while HAS1+ stromal cells expanded and were distinct from α-SMA+ myofibroblasts.
HAS1+ fibroblasts display enhanced migration, FAP expression, and reduced profibrotic marker expression.
HAS2+ fibroblasts exhibit a contractile myofibroblast phenotype with high EDA-FN and COL1A1 expression.
The study identifies HA as a regulator of stromal fibroblast phenotype and associates HAS1 and HAS2 with divergent fibrotic outcomes after kidney injury.
This study looked at hyaluronan (HA), a sugar-based molecule in the space between cells, and the enzymes that make it (HAS1 and HAS2) in the kidney. Healthy adult kidney tissue has almost no HA in its supportive tissue (stroma). After a kidney injury caused by temporary loss of blood flow, HA built up and the enzyme HAS2 increased, which was associated with long-term scarring (fibrosis). In contrast, during kidney development and during recovery from injury, a different enzyme, HAS1, was prominent. Cells expressing HAS1 were a separate population from scar-forming myofibroblasts. In human fibroblast experiments, HAS1 cells moved more readily, expressed fibroblast activation protein, and showed lower levels of scarring-related markers. HAS2 cells looked like contractile, scar-promoting myofibroblasts with high levels of fibronectin EDA and collagen I. This research suggests that which HA-making enzyme a fibroblast uses may shape whether kidney injury leads to scarring or to repair. It points to HAS1 and HAS2 as potential markers or targets for future work on kidney fibrosis, though this study does not test any treatment in patients.
Grigorieva I, Midgley A, Brown C, Chavez G, Szomolay B, Williams A, et al.. (2026). Hyaluronan Synthase Isoforms Direct Distinct Patterns of Fibroblast Activation Linked to Fibrosis Progression Versus Resolution Following Renal Ischaemia.. Biomolecules. https://doi.org/10.3390/biom16101442