Proteolytic activation of hepatocyte growth factor in response to tissue injury.

Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes and renal tubular epithelial cells and may play an important role in regeneration following hepatic and renal injury. HGF is first synthesized as a single chain precursor which is then converted to a heterodimeric form by proteolytic processing. This proteolytic conversion is required for HGF to function as a mitogen. In this study, we examined whether the proteolytic activation of HGF occurred in response to hepatic and renal injury. HGF remained as an inactive single chain form in the liver, kidney, lung, and spleen of normal rats. The production of HGF markedly increased in the liver after hepatotoxin treatment and in the kidney after nephrotoxin treatment. A significant portion of the increased HGF was converted to the active heterodimeric form, whereas in other tissues, conversion did not occur although the production of HGF increased in some of them. Furthermore, an enzymatic activity that converts the single chain form of HGF to the active heterodimeric form was detected in the injured liver but not in the normal liver. These results indicate that HGF is proteolytically activated in response to tissue injury, and this activation is mediated by an enzymatic activity which is induced exclusively in the injured tissues. Thus, the proteolytic activation system functions in vivo as a mechanism for localizing HGF activities to injured tissues.