HYALURONAN INDUCES MONOCYTE CHEMOATTRACTANT PROTEIN-1 EXPRESSION IN RENAL TUBULAR EPITHELIAL-CELLS

Hyaluronan (HA) is a nonsulfated glycosaminoglycan that accumulates in the renal interstitium in immune-mediated kidney diseases. The functi onal significance of such HA deposition in the kidney has not been elu cidated. Several studies have suggested that HA may exhibit proinflamm atory effects. Since chemokines such as monocyte chemoattractant prote in-1 (MCP-1) play an important role in the recruitment of leukocytes i n renal injury, this study tested whether HA and its fragments could p romote MCP-1 production by renal parenchymal cells. Mouse cortical tub ular cells were stimulated with fragmented HA or with high molecular w eight HA (Healon) in vitro and were examined for MCP-1 expression. Fra gmented HA, but not Healon, increased MCP-1 mRNA within 30 min with a peak after 2 h. In addition, a 10-fold increase of MCP-1 protein in th e supernatant was found after a 6-h stimulation with fragmented HA. Th e enhanced MCP-1. mRNA and protein expression in response to HA was do se-dependent between 1 and 100 mu g/ml. Upregulation of MCP-1 protein production could be blocked by preincubation with actinomycin D or cyc loheximide, suggesting that MCP-1 mRNA and protein expression in respo nse to HA are based on de novo synthesis. The HA-stimulated MCP-1 prod uction was also inhibited with anti-CD44 antibodies, suggesting that M CP-1 is upregulated at least in part by signaling through CD44. In sum mary, fragmented HA markedly stimulates renal tubular MCP-1 production by mechanisms that involve binding to the HA receptor CD44. It is hyp othesized that the accumulation of HA in immune renal injury could par ticipate in the recruitment and activation of inflammatory cells in vi vo through production of MCP-1.