Hyaluronic acid promotes calcium oxalate crystal growth, crystal-cell adhesion, and crystal invasion through extracellular matrix

Hyaluronic acid (HA), a macromolecule in glycosaminoglycans family, is normally excreted into the urine with a small amount, but with much greater level in the urine from stone patients (formers). However, its precise roles in kidney stone pathogenesis remained unclear. This study examined its roles in calcium oxalate (CaOx) kidney stone formation processes, including neocrystallization, crystal growth, adhesion, internalization, aggregation and invasion. The results showed that HA (1, 10, 100, 1000, or 10,000 ng/ml) did not affect CaOx neocrystallization, aggregation, and internalization into MDCK distal renal tubular cells. However, HA significantly promoted CaOx crystal growth (at 10-10,000 ng/ml), adhesion onto renal tubular cells (at 1000-10,000 ng/ml), and invasion through extracellular matrix (ECM) (at 1-10,000 ng/ml). Analysis of the plasminogen sequence revealed six sites with the HA-binding motif "B(X7)B" that explained the HA ability to trigger the plasminogen-plasmin system required for crystal invasion. In summary, our systematic analysis highlights the promoting effects of HA on CaOx crystal growth, crystal-cell adhesion and invasion through the ECM. These effects of HA may explain its high level in the stone patients' urine, thereby promoting the stone formation.