Thrombin stimulates production of transforming growth factor-beta by cultured human mesangial cells

Fibrin formation within the glomeruli occurs in various forms of human andexperimental glomerulonephritis and it may play an important role inprogressive glomerular injury. Transforming growth factor-beta (TGF- beta)has been shown to participate in the glomerular accumulation ofextracellular matrix in glomerulonephritis. We investigated whetherthrombin, an important coagulation factor, could modulate the production ofTGF-beta by cultured human mesangial cells (HMC). TGF- beta levels in theculture supernatants were measured by ELISA using a specific antibody. TheTGF-beta concentration was significantly increased by incubation of HMCwith thrombin in a time-dependent manner. The stimulating effect ofthrombin on TGF-beta was inhibited by addition of hirudin (a naturalthrombin inhibitor) and argatroban (a synthetic thrombin inhibitor). Inaddition DFP-inactivated thrombin, which has no enzymatic activity, did notstimulate TGF-beta production. A protein kinase C inhibitor (H7) and atyrosine kinase inhibitor (herbimycin A) also inhibited thrombin inducedTGF-beta production. These findings suggested that thrombin may modulatethe synthesis of TGF-beta via protein kinase C- and tyrosinekinase-dependent mechanisms in cultured HMC. Thus thrombin may participatein the accumulation of extracellular matrix in glomeruli through theaugmentation of TGF-beta production.