Mesangial cells (MCs) are essential for normal renal function through the synthesis of their own extracellular matrix, which forms the structural support of the renal glomerulus. In many renal diseases this matrix is reorganized in response to a variety of cytokines and growth factors. This study examines proteoglycan and hyaluronan (HA) synthesis by MCs triggered by proinflammatory agents and investigates the effect of an exogenous HA matrix on matrix synthesis by MCs. Metabolic labeling, ion exchange and size exclusion chromatography, Western blotting, and immunocytochemistry were used to identify changes in matrix accumulation. When incubated with interleukin-1, platelet-derived growth factor, or fetal calf serum, MCs initiated rapid HA synthesis associated with the up-regulation of HA synthase-2 and increased the synthesis of versican, perlecan, and decorin/biglycan. HA was both released into the medium and incorporated into extensive pericellular coats. Adding exogenous HA to unstimulated cells that had undetectable pericellular coats of HA selectively reduced perlecan and versican turnover, whereas other proteoglycans were unaffected. These results suggest that high levels of HA in the mesangium in disease is a mechanism controlling the accumulation of specific mesangial matrix components. HA may thus be an attractive target for therapeutic intervention.