The glomerulopathy of monoclonal immunoglobulin light chain deposition disease is a progressive disorder characterized by accumulation of monoclonal light chains and matrix proteins in the mesangium. To define the role of light chains in this process, cultured rat mesangial cells were exposed to different light chains and human albumin. Two light chains were purified from the urine of patients who had biopsy-proven light chain deposition disease. These proteins inhibited mesangial cell proliferation and increased production of matrix proteins, including type IV collagen, laminin, and fibronectin. By immunocytochemistry and bioassay, transforming growth factor-beta (TGF-beta) production and activity increased when mesangial cells were exposed to these proteins. Furthermore, anti-TGF-beta antibody abolished the inhibition of cell proliferation and the increase of extracellular matrix protein production caused by these light chains. These findings were not observed in mesangial cells exposed to human albumin and two other light chains previously characterized to be tubulopathic. We concluded that the glomerulopathic light chains increased TGF-beta, which inhibited mesangial cell proliferation and increased matrix protein production. Together with overexpression of TGF-beta in affected glomeruli of light chain deposition disease, light chain-mediated stimulation of mesangial cells to produce TGF-beta appears to be a key pathological mechanism of this disease.