Hyperlipidemia has been associated with glomerulosclerosis and a glomerular monocyte infiltrate in models of progressive renal insufficiency. The pathogenesis of hyperlipidemia-induced renal injury remains unknown. We postulated that the effect of hyperlipidemia may be mediated through LDL-induced activation of mesangial cells, which have recently been shown to possess LDL receptors. To test this hypothesis, cultured human mesangial cells were co-incubated with human LDL. Monolayers treated with LDL demonstrated a greater level of tissue culture supernatant fibronectin than control mesangial cells. This correlated with enhanced expression of fibronectin mRNA in LDL-treated mesangial cells. Additionally, LDL conditioning of mesangial cells caused a dose- and time-dependent increase in the expression of monocyte chemoattractant protein-1 mRNA, a monocyte specific chemotactic factor, as well as an increase in the monocyte chemotactic activity of mesangial supernatants. Thus, the deleterious effects of hyperlipidemia on the kidney may be mediated by the mesangial cell through an increase in production of mesangial matrix and recruitment of inflammatory cells to the glomerulus.