Deposition of type III collagen protein is increased when cultured rat mesangial cells are cultured in media containing high glucose concentrations. Possible mechanisms for this effect include the production of growth factors, such as PDGF and TGF-beta, and the formation of abnormal glucose-protein adducts called advanced glycosylation end products (AGEs). In our studies, neutralizing antibodies to PDGF and TGF-beta prevented increased type III collagen deposition by mesangial cells exposed either to high glucose media or to low glucose media containing AGEs. Daily addition of PDGF or TGF-beta stimulated type III collagen production. However, while co-incubation with the TGF-beta Ab prevented PDGF-stimulated type III collagen production, the PDGF Ab did not prevent TGF-beta-stimulated type III collagen production. Daily addition of PDGF or TGF-beta stimulated, while AGEs inhibited, mesangial cell proliferation after 96 hours. We propose that high extracellular glucose and AGEs stimulate type III collagen production by pathways that involve the intermediate formation of PDGF and TGF-beta by mesangial cells. PDGF may increase type III collagen production by stimulating the intermediate production of TGF-beta. Exposure to high glucose, AGEs, or TGF-beta also leads to impaired mesangial cell proliferation. The autocrine effects of TGF-beta and PDGF play important roles in the effects of high extracellular glucose and AGEs on cultured mesangial cells.