Accumulation of extracellular matrix is a characteristic of diabetic nephropathy, and advanced glycation end products (AGEs) are considered to play an important role in the mechanism. To investigate the involvement of the receptor for AGE (RAGE) in upregulation of type IV collagen by AGEs, we applied the hammerhead ribozyme for targeting RAGE. We established a stable mouse mesangial cell line that produces the RAGE-specific ribozyme (Rz-RAGE). Both the RAGE mRNA and protein were decreased in the cell line. The amount of type IV collagen mRNA increased by AGEs' treatment in control cells. In contrast, the increase of type IV collagen induced by AGEs was not observed in the Rz-RAGE-producing cells. We conclude that the induction of type IV collagen by AGEs is mediated by RAGE and this mechanism could be involved in diabetic nephropathy. This study also suggested the experimental/therapeutic potential of hammerhead ribozymes.