Hepatocyte growth factor (HGF), a most potent growth factor for mature hepatocytes may act as a trigger for liver regeneration. We reported that HGF strongly stimulates DNA synthesis of rabbit renal tubular cells in secondary culture (Igawa, T., Kanda, S., Kanetake, H., Saitoh, Y., Ichihara, A., Tomita, Y., and Nakamura, T. (1991) Biochem. Biophys. Res. Commun. 174, 831-838). To investigate whether or not HGF is involved in renal regeneration, we examined changes in HGF mRNA, HGF activity, and HGF receptor in the rat kidney following unilateral nephrectomy or treatment with carbon tetrachloride (CCl4). In the intact kidney, the HGF mRNA increased markedly reaching a maximum 6 h after unilateral nephrectomy, followed by an increase of HGF activity at 12 h after the surgery. The marked increase in HGF mRNA and HGF activity was also found in the kidney of rats treated with CCl4. Results of in situ hybridization suggested that cells producing HGF in the kidney are endothelial cells. The number of HGF receptors on renal plasma membranes decreased to 30% of the normal value 12 h after unilateral nephrectomy, with no change in the Kd value. The HGF receptor was greatly diminished 24 h after the operation, and recovery to 60% of the normal level was evident 1 week after the operation. Because the decrease in HGF binding may result from internalization of the HGF receptor, the HGF may bind to its receptor in vivo and act as a mitogen for renal epithelial cells. HGF may function as a renotropic factor during renal regeneration after kidney injury.