Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro

The interaction of hepatocyte growth factor (HGF) with c-Met has been impli cated in morphogenesis of the kidney, lung, mammary gland, liver, placenta, and limb bud. HGF is secreted as an inactive zymogen and must be cleaved b y a serine protease to initiate Met signaling. We show here that a serine p rotease specific for HGF, HGF activator (HGFA), is expressed and activated by the ureteric bud of the developing kidney in vivo and in vitro. Inhibiti on of HGFA activity with serine protease inhibitors reduced ureteric bud br anching and inhibited glomerulogenesis and nephrogenesis. Activated HGF res cued developing kidneys from the effects of inhibitors. HGFA was localized around the tips of the ureteric bud in developing kidneys, while HGF was ex pressed diffusely throughout the mesenchyme. These data show that expressio n of HGF is not sufficient for development, but that its activation is also required. The localization of HCFA to the ureteric bud and the mesenchyme immediately adjacent to it suggests that HGFA creates a gradient of HGF act ivity in the developing kidney. The creation and shape of gradients of acti vated HGF by the localized secretion of HGF activators could play an import ant role in pattern formation by HGF responsive tissues.