Substantial in vivo evidence exists to implicate the macrophage (M phi) in modulating mesangial expansion and glomerulosclerosis (GS) following renal injury. We studied in an in vitro system how M phi activation via Fc-receptor-mediated endocytosis, such as occurs in immune complex-mediated disease states, may influence the effect of M phi secretory products (MSP) on mesangial cell (MC) proliferation and matrix synthesis. MSP from M phi incubated with immunoglobulin G (IgG) complexes caused significantly greater (P < 0.001) enhancement of MC [3H]thymidine incorporation compared with MSP from unstimulated M phi or from M phi activated via nonspecific endocytosis (P < 0.001). MSP from M phi incubated with IgG complexes plus the inhibitor of endocytosis cytochalasin B showed an attenuated effect on MC proliferation (P < 0.02). MSP were also found to enhance MC matrix synthesis (P < 0.001). These data demonstrate that MSP can play a direct role in mesangial expansion by increasing both MC proliferation and matrix synthesis. Surface binding alone of IgG complexes may not be sufficient to activate M phi and enhance their mitogenic effect on MC as endocytosis appears to be required. These findings lend in vitro support to a potential role for the M phi in the process of mesangial expansion and GS following renal injury.