Renal hypertrophy develops early in the course of diabetes and has been linked to progressive renal disease. Although the mechanism of renal hypertrophy is unknown, evidence suggests that local alterations in the production of one or more growth factors and/or their receptors are crucial to this process. In this study, we demonstrate that the c-met protooncogene product, a tyrosine kinase receptor for hepatocyte growth factor (HGF), is increased in the kidney of the diabetic rat. Northern blot analysis showed that renal expression of the c-met gene was substantially increased in rats made diabetic by administration of streptozotocin. Immunohistochemical studies revealed that the protein for c-met was concordantly elevated in cortical and medullar tubular epithelium following the onset of diabetes. Moreover, in vitro studies demonstrated that short-term exposure to high glucose concentration markedly stimulated c-met expression in cultured proximal tubular (opossum kidney) and inner medulla collecting duct cells (mIMCD-3). The results of enhanced renal expression of c-met together with elevated HGF indicate that the HGF/c-met system is markedly activated in the diabetic rat. These findings suggest that the HGF/c-met system may play a role in the diabetic renal hypertrophy.