Characterization of hepatocyte growth factor activator inhibitors which are being developed for a medicine

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It is reported that overaction of hepatocyte growth factor (HGF) causes kidney injury. Thus, it is required to develop a medicine which suppresses overaction of HGF. We identified two novel protease inhibitors (HAI-1 and HAI-2) which inhibit the activity of HGF activator. In this study, we examined whether these inhibitors could function as a medicine for diseases caused by overaction of HGF, and obtained the following results.1. HAI-1 has two Kunitz domains which are thought to be functional domains for the protease inhibitory activity of HAI-1. To determine the roles of the Kunitz domains in the inhibitory activity of HAI-1 against HGF activator, we constructed various human HAI-1 mutant proteins and examined their inhibitory activity against HGF activator. The N-terminal Kunitz domain had potent inhibitory activity, whereas the C-terminal Kunitz domain had only very weak activity. HAI-2 also has two Kunitz domains. We also examined the roles of Kunitz domains in the inhibitory activity of mouse HAI-2 against HGF activator. Unlike human HAI-1, the C-terminal Kunitz domain had potent inhibitory activity, whereas the N-terminal Kunitz domain had less activity. Therefore, it is necessary to examine which Kunitz domain of HAI-1 and HAI-2 is suitable for a medicine.2. To investigate whether the Kunitz domain of HAI suppresses activation of HGF in vivo, it is required to establish an assay system using experimental animals. We examined whether injection of HGF activator into rats induces activation of HGF. Injection of HGF activator induced activation of HGF in the liver of partially hepatectomized rats. This injection also induced liver regeneration. Therefore, this system would be useful to assay the inhibitory activity of the Kunitz domain of HAI.